Open access peer-reviewed chapter
Abstract
Prolactin (PRL) is a peptide and pleiotropic hormone with more than 300 associated functions such as maternal behavior, lactation, osmoregulation, angiogenesis, and the immune system. It is associated with several functions in the brain, including lactation, cognition and memory, maternal behavior, and neurogenesis. PRL reportedly plays an important role in neuroprotection against excitotoxicity caused by glutamate (Glu) and kainic acid (KA) damage in vitro and in vivo models. However, the molecular mechanisms involved in the neuroprotective effects of PRL are unclear. Despite this, data suggest the involvement of PI3K/AKT, and GSK3β/NF-κB signaling pathways, which are involved in neuroprotection. In addition, PRL inhibits Glu- and KA-induced increase by intracellular Ca2+ concentration, leading to neuronal survival. We also discuss current knowledge on the role of PRL in neurodegenerative diseases. New avenues of research into the protective mechanisms of PRL and its potential therapeutic effects on the brain under pathological and physiological conditions are needed.
Keywords
- prolactin
- neuroprotection
- excitotoxicity
- signaling pathways
- calcium regulation
- NMDA/AMPA channels
- neurogenerative disease
1. Introduction
Current research aims to find molecules or compounds that are capable of protecting cells from damage and subsequent cell death, which may cause pathophysiology or neurodegenerative diseases (NDs) [1, 2, 3, 4]. Excitotoxicity is cell damage that can trigger death by apoptosis and necrosis and is involved in multiple neurological conditions, including epilepsy, stroke, and neurodegenerative disorders [4, 5, 6, 7]. These neurological conditions are a heterogeneous group of diseases with different clinical phenotypes and genetic etiologies that are characterized by the gradual loss of specific populations of neuronal cells and dysfunction of proteins that influence several signaling cascades that cause neuronal damage [1, 4, 5, 6]. In addition, these conditions share common pathogenic mechanisms, including the deregulation of intracellular calcium (Ca2+) homeostasis, the activation of nitric oxide synthesis, and the activation of reactive oxygen species (ROS), which damage different biomolecules (lipids, proteins, carbohydrates, and nucleic acids), altering cell function and inducing cell death, leading to progressive neurodegeneration [1, 8, 9]. However, there are few natural compounds capable of exerting neuroprotective effects against excitotoxicity such as curcumin [10], vitamins [11], and hormones. Recently, prolactin (PRL), a peptide hormone, has been in the limelight for its role in neuroprotective processes [1, 12, 13, 14]. PRL is relevant due to its neuroprotective effects
2. Prolactin
To understand the neuroprotective effects of PRL, it is necessary to know its characteristics and mechanism of action. Since its discovery in the 1930s by the biologist Oscar Riddle [17, 18], it has been considered a hormone that controls the production and secretion of milk, and nowadays, it is known as a multifunctional endocrine hormone of great interest in the scientific community [19, 20].
PRL is known to have strong structural homology with growth hormone and placental lactogen, which belongs to a large family of hematopoietic cytokine proteins characterized by having a tertiary structure composed of four antiparallel α-helices [21, 22]. Likewise, the mature PRL protein of pituitary origin is composed of 197 and 199 amino acids in rats and humans, respectively, with three disulfide bonds located in similar positions in both species [19, 23]. It is widely accepted that PRL is synthesized in the anterior lobe of the pituitary by specialized cells called lactotrophs [21, 24, 25]. It is now known that it can also be produced by other extrapituitary cells [16, 26, 27]. In addition, transcriptional regulation of pituitary and extrapituitary PRL expressions are controlled by a proximal and a distal promoter region, respectively [16, 22, 27].
PRL is present in all mammals [22, 23, 28] and is encoded by a single gene (PRL) composed of five exons and four introns in the majority of the species [22, 25]. Nevertheless, at the molecular level, its expression and regulation are tissue-specific because several isoforms have been described that result from proteolytic cleavages, alternative splicing, or posttranslational modifications, such as glycosylation, phosphorylation, deamidation, and association with other circulating proteins, thus modifying its biological activity [16, 21, 29].
PRL can have various forms of modification, for example, high molecular mass PRL, such as “big PRL” and “big big PRL” (also known as macroprolactin) of approximately 100 kDa; however, these forms show lower activity and could participate in the storage, modification, and release of PRL [16, 21]. There are those with low molecular mass of 14, 16, and 22 kDa that are generated from proteolytic cleavage of the 23 kDa pituitary PRL [17, 18, 22]. In addition, PRL can form dimers, polymers, and aggregates, and its actions are mediated by its receptor [18, 29]. See Figure 1 where the PRL structure and its receptor are described.
Figure 1.
The possible molecular mechanisms of action of PRL-induced neuroprotection against excitotoxic damage. (A) the PRLR heterodimer binds to its ligand activating the JAK2 kinase, which phosphorylates PI3K, subsequently it promotes the activation of AKT. The blue line shows the activation of PI3K/AKT signaling pathway (B) which may promote NF-κB translocation to the nucleus increasing expression of survival genes, such as
3. Prolactin receptors
PRL actions are initiated by binding to a homodimer of the prolactin receptor (PRLR), forming a heterotrimeric complex with the ligand [27, 29].
Rat and human PRLRs are membrane proteins belonging to the class I cytokine receptor superfamily [16, 27, 29]. These receptors are single-pass transmembrane proteins that lack intrinsic tyrosine kinase activity and can be phosphorylated by cytoplasmic proteins [16, 27, 29]. They are composed of three domains: extracellular, with two regions, designated S1 and S2 (or D1 and D2) that together form the ligand binding site; transmembrane, which is identical in both species; and intracellular or cytoplasmic, of variable length and composition [20, 22, 27, 28]. PRLRs are mainly related to the activation of the JAK2-STAT5 signaling pathway but can initiate other signaling cascades, in addition to being ubiquitously expressed in various tissues [16, 24, 29].
Multiple PRLR isoforms resulting from alternative splicing of the primary mRNA transcript have been identified in rodents and humans [22, 29, 31]. These isoforms have identical extracellular and transmembrane domains, only differing in length and sequence in the intracellular domains [20, 32]. Three different isoforms of PRLRs have been identified in rats: short (PRLR-S), intermediate (PRLR-I), and long (PRLR-L) [16, 22], while a soluble isoform has been described in humans. The most studied isoforms are the PRLR-L, PRLR-I, and PRLR-S due to their distribution and expression [16, 27].
Regarding the PRL activation pathway, the binding of PRL to the PRLR-L triggers different signaling pathways, the main signaling cascade being
Finally, it should be noted that the PRLR is expressed in several tissues such as the mammary gland, gonads, liver, kidneys, adrenal gland, brain, heart, lungs, pituitary gland, uterus, skeletal muscle, skin, and cells of the immune system [16, 18, 23, 25, 29]. Despite being found in many tissues, this article focuses on PRLR expression in the brain, where it has been reported in several brain areas such as the olfactory bulb, corpus callosum, choroid plexuses, amygdala, hypothalamus, thalamus, cerebral cortex, and hippocampus [15, 27, 29].
4. Prolactin functions
Although PRL has been predominantly related to pituitary lactotrophs, it is now recognized that it is also expressed and secreted in other tissues [22, 23, 25]. Therefore, it is considered a pleiotropic hormone with more than 300 known physiological effects [22, 23] such as reproduction, lactogenesis, immunomodulation, angiogenesis, energy metabolism, osmotic balance, and development regulation [27, 35, 36]. It has also been reported that PRL can cross the blood-brain barrier [26, 36], and its effects on the brain depend on factors such as age, sex, and reproductive status of the species [27, 31]. Importantly, PRL has been reported to regulate specific neuronal circuits and participate in many brain functions, including maternal behavior, energy balance, food intake, sleep, anxiety, neurogenesis, migraine, and pain [16, 18, 36, 37, 38].
Interestingly, a transcriptomic analysis by Cabrera-Reyes et al. [15] indicated that PRL induces the expression of different sets of genes involved in brain processes related to learning, behavior, memory, neuroprotection, neurodevelopment, neurogenesis, remodeling, plasticity, and sleep/wake-up regulation.
5. Prolactin in neuroprotection
As mentioned above, PRL is related to more than 300 biological actions, highlighting its role as a neuroprotective hormone against excitotoxicity, which has been described in both
The concept of excitotoxicity was originally suggested by Olney et al. [40] to refer to the ability of glutamate (Glu) to induce neuronal damage [41]. Nowadays, this term generally refers to neuronal injury and death, resulting from prolonged exposure to Glu and excitatory amino acids [2, 42]. This exposure induces overactivation of ionotropic glutamatergic neuronal receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptor, and kainic acid [43, 44]. Overactivation causes an increase in Ca2+ intracellular concentration, which, in turn, induces the activation of Ca2+-dependent enzymes and the generation of free radicals (ROS). When there is an excessive increase in Ca2+ and ROS, mitochondrial membrane potential decreases, releasing mitochondrial factors Cytochrome-C and apoptosis-inducing factor, triggering apoptosome complex activation
Cabrera-Reyes et al. [15] used
Beside, neuroprotection by PRL was analyzed using primary cultures of hippocampal neurons, proving that the hormone performs its functions through interaction with its receptor [13] and that administrating PRL before excitotoxic damage by Glu prevents cell death and mitochondrial dysfunction, inhibits the increase in intracellular Ca2+ levels triggered by the excitotoxic insult, and promotes the activation of the transcriptional factor NF-κB, which induces overexpression of the antiapoptotic protein Bcl-2 in hippocampal neurons [14]. In addition, molecular signaling pathways, involving PI3K/AKT and NF-κB/GSK3β, could be implicated in the molecular mechanisms that explain the effects of PRL against excitotoxicity and neuroprotection [14, 16, 27].
Recently, Molina-Salinas et al. [30] demonstrated that PRL activates the PI3K/AKT signaling pathway during Glu excitotoxicity, which promotes neuronal survival through AKT activation and GSK3β/NF-κB upregulation, resulting in the induction of
6. Prolactin and its relation to neurodegenerative diseases
NDs have a common characteristic; the progressive loss of neuronal populations due to the changes in their structure and function [50] that lead to neuronal death. These pathologies also have similar cellular mechanisms and histopathological features [51] identified as an aberrant protein process and in their trafficking and aggregation in neurons by dysregulation in their ubiquitin–proteasomal and autophagosome/lysosomal systems. Other mechanisms include the formation of extracellular plaques that induce neuroinflammation through microglia activation [52, 53, 54] and increase oxidative stress levels that result in neuronal progressive damage. Moreover, as discussed previously, excitotoxicity is involved in NDs [42, 55].
NDs may be grouped based on their similarities: first, clinical features related to the anatomic distribution of neurodegeneration (frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), and second, by protein biochemical abnormalities [56, 57]. It is well-known that the most common NDs are amyloidosis, tauopathies, and α-synucleinopathies [58]. Interestingly, these protein abnormalities can be present before clinical manifestations begin. Therefore, it is important to find new treatments and develop strategies against these diseases. In this sense, PRL as a neuroprotective agent may play a role against neurodegenerative pathologies. In the next sections, we will discuss how PRL participates in these diseases.
6.1 Evidence of the role of prolactin in Alzheimer’s disease
Alzheimer’s disease (AD) is a well-known chronic neurodegenerative disease whose main targeted brain areas are the medial temporal lobe and associative neocortical structures. Over the years hallmarks of AD, research have been described, among them is the accumulation of the amyloid-beta peptide (Aβ) in the brain, which results in aggregation of this insoluble oligomer and protofibrils. Moreover, cytoskeletal changes derived from hyperphosphorylation of microtubule-associated Tau protein in neurons are a feature. Overproduction of Aβ results from a failure in proteolytic cleavage of the amyloid precursor protein (APP). Accumulation of fibrillary Aβ results in senility and neurotic plaque formation. This event and the incapability of Aβ clearance from the brain trigger an extracellular accumulation of Aβ, and consequently oxidative stress, cytoskeletal changes, neuronal dysfunction, and finally neuronal death [59, 60, 61].
In a pioneering study describing PRL regulation in AD patients with dementia, subjects referred to as having Alzheimer’s senile dementia (SDAT) and their respective control were treated with metoclopramide (a dopamine-blocking drug). The results showed no difference in PRL levels between patients with dementia and controls after 24 hours of treatment. However, 30 min after metoclopramide injection, PRL levels increased significantly, suggesting that PRL regulation in dementia caused by AD is controlled through the tuberoinfundibular pathway [62].
In contrast, successive studies have reported that serum PRL levels do not respond to thyrotropin-releasing hormone (TRH) stimulation in subjects with multi-infarct dementia and patients with SDAT. Indeed, PRL concentration was similar in these types of dementia. In addition, the authors reported that there was no correlation between dementia degradation and PRL level [63]. Despite the limitations of these studies due to the small number of patients included, an interesting relationship between dementia caused by AD and serum/plasma PRL concentrations was found. However, the correlation between PRL and AD has not yet been studied in depth, and other risk factors, such as age and sex, have not been considered in these investigations.
Other evidence supporting PRL participation in the pathophysiology of neurological diseases was reported in a common AD model with APPswe/PS1dE9 double transgenic male murine. PRL and PRLR genes were downregulated during the early stages of amyloidogenesis in the hippocampus compared to wild-type mice [64], suggesting that PRL possibly participates in the pathophysiology of AD.
In this regard, PRL has been associated with regulating some proteins and even signaling pathways that may be involved in the development and progression of AD, such as the case of glycogen synthase kinase-3 (GSK3). In AD, the PI3K/AKT signaling pathway is reduced, its inactivity leads to increased hyperphosphorylation of Tau, which is important for microtubule stability [65, 66]. AKT promotes GSK3 inhibition and subsequent reduction of Tau phosphorylation. Inactivation of GSK3 correlates with elevated levels of PRLR protein [67], which could explain in part why a lower concentration of PRL is associated with AD. Notably, AKT is one of the main signaling pathways used by PRL in the brain [16].
In addition, PRL displays a neuroprotective role mediated by Tau regulation during female neurodegeneration in response to PI3K/AKT/GSK3β pathway activation [68] and may promote neuronal survival [30]. Moreover, lactation as a physiological process induces a regulation of GSK3-α and p-Tau levels in lactating rats exposed to restraint stress. Lactating rats that were sacrificed 24 h after exposure to restraint stress had an increase of p-Tau in contrast to the restraint-stressed lactating rats sacrificed only 20 min after stress exposure, which showed reduced phosphorylation levels [69]. Thus, these experiments suggest that the regulatory dynamics between PRL hormone and GSK3 expression might play a role in AD pathology.
Another association between PRL and NDs is TRH, which is a well-known regulator of PRL secretion in tuberoinfundibular dopamine neurons [70, 71]. Like other hormones, such as PRL, TRH administration has been studied in neuroprotection [72]. It has been reported that reduction of GSK3β activity induced a reduction of Tau phosphorylation, and TRH gene depletion promoted the highest levels of GSK3β protein in cultured rat hippocampal neurons. Interestingly, the downregulation of TRH and its receptors has been implicated as a risk factor for developing AD and dementia [73, 74, 75]. Moreover, in women, the lowest and highest levels of serum TSH concentrations increased the risk of developing AD, but this correlation was not observed in men [76]. These observations suggest the possible sex-differential role that hormones play in neurodegenerative conditions.
Diverse approaches to identifying possible biomarkers as therapy triggers for AD have been reported [77]. Interestingly, PRL was proposed as a biomarker in a novel study showing a robust protein analyte from data of three cohorts to find analytes using Aβ1–42 in cerebrospinal fluid (CSF). PRL level was higher in patients with low Aβ1–42 levels compared to other groups [78]. Although this study suggests a possible involvement of PRL in AD pathology, the authors propose further studies to determine its usefulness in diagnosis and benefits in the treatment of AD.
On the other hand, melatonin, cortisol, homocysteine, and PRL plasma concentrations were measured in 85 patients. Notably, increased levels of PRL plasma were reported in subjects with AD and dementia [79]. Beside, a study indicated that both women and men with AD showed an increase in TSH, PRL, and GH plasma levels [60]. Conversely, in another study with elderly patients over 60 years, PRL serum levels did not change significantly [80]. These studies highlight the difficulty of using PRL diagnosis or even to determine the progression of AD, where factors, such as age, gender, mental, and physiological condition, are involved and may be interrelated.
In summary, PRL could promote different effects in NDs depending on gender. In this regard, gender differences are observed in these pathologies, indeed, the incidence rate of AD in women is higher than in men [81]. However, Parkinson’s disease (PD) is more prevalent in males than in females [82, 83]. Thus, it is necessary to further explore the neuroprotective role of PRL in both sexes with aging.
6.2 Prolactin and its role in Parkinson’s disease
PD is one of the most common neurodegenerative disorders and is a pathology characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Its molecular features are the presence of misfolded alpha-synuclein protein as a cytoplasmic inclusion, named Lewy bodies, in neurons. Genetic factors related to mutation in genes, such as
Many reports indicate the risk of developing PD is higher in men than in women [82, 83]. Hormone actions, such as estrogen on dopaminergic neuron degeneration, as neuroprotective agents in PD have been widely discussed [88, 89]. Extensive reviews of estrogen as a neuroprotective hormone in PD have been made [90, 91]. Additionally, a study performed in men with PD confirmed increased PRL levels compared to the controls [83]. Thus, PRL probably has different effects on neurodegenerative diseases depending on gender. Thus, the question of whether other hormones related to neuroprotection, such as PRL, have a similar effect in PD opens new avenues for its study. Here, we discussed the role of PRL in PD.
Since PRL secretion is mostly regulated by the dopaminergic pathway [17, 92], many of the pioneer studies were focused on elucidating the relationship between PRL and PD in terms of their interaction with drugs used in PD treatments. For example, Eisler et al. [93] measured PRL and TRH serum levels in parkinsonian patients. Interestingly, PRL and the TRH-induced rise in PRL were normal in patients with PD, whereas levodopa (L-dopa) and carbidopa treatment suppressed PRL concentration in PD patients. These results show how dopaminergic control is in its prime regulation. However, dopaminergic control of PRL in patients with NDs is more complex.
Plasma PRL levels were examined in subjects with PD during the night. Additionally, sleep was assessed to determine the impact of PRL on PD development. The authors reported that plasma PRL levels decreased compared to the controls. Interestingly, these plasma PRL concentrations showed a similar secretion pattern observed in Huntington’s patients [94]. Patients with PD associated with major depression and nondepressed Parkinsonians were examined, and PRL and cortisol responses to treatment with fenfluramine (a serotonin-releasing agent) were measured. PRL levels were reduced in patients with PD relative to the controls. Interestingly, PRL was lower in PD patients with major depression compared with the nondepressed patients [95]. Similarly, plasma PRL levels increased with Madopar administration (a combination of L-dopa and benserazide) [96].
Based on the above studies, there are remarkable changes in PRL levels during the progression of PD pathology in response to the conditions of this ND, such as treatment and severity level, which could explain the discrepancies between studies. For example, levels of sex hormones, such as estradiol, testosterone, and PRL, correlated with improvement in quality of life in a study performed in male PD patients. Surprisingly, PRL levels were significantly increased in the PD group. This suggests a possible involvement of PRL in PD; however, future research is still required to elucidate the role of PRL in PD. As the authors mentioned, a limitation of their research was that the influence of benserazide or carbidopa on the measurement of PRL levels was not taken in consideration [83].
A recent study to discover an accessible biomarker analyzed more than 200 CSF samples using sensitive mass spectrometry (MS)-based proteomics from two independent cohorts. The authors reported specific proteins deregulated in PD patients
Conversely, studies have reported decreased levels in patients with PD. For example, PRL levels were lower in patients with idiopathic PD (IPD) compared to those with multiple system atrophy [98]. In addition to these results, ovariectomized hemiparkinsonian rats treated with estradiol and L-dopa expressed synaptotagmin IV (Syt IV), a gene highly co-expressed with PRL. The authors reported that in this hemiparkinsonian model, high levels of serum from estradiol promoted the upregulation of Syt IV, and consequently of PRL, whereas L-dopa treatment downregulated Syt IV, but no in PRL expression was reported [99]. Interestingly, estradiol and L-dopa are well-known regulators of PRL secretion from the pituitary gland [17]. Beside, in Holstein steer models, L-dopa treatment promotes decreased PRL levels in CSF samples [100]. These results suggest a PRL dysregulation of the dopaminergic pathway in PD.
It is well-known that dysregulation of PRL and TRH levels in patients with PD might be a consequence of damage in TIDA neurons [101]. PRL is regulated by hypothalamic dopaminergic mechanisms. Interestingly, the main drugs used for PD treatment are dopamine precursors: (L-dopa) dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, and rotigotine), monoamine oxidase inhibitors (selegiline and rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone and tolcapone). For an extensive review see [101]. Notably, PRL has negative and positive interactions with those drugs; however, more research is required to understand the effects that PRL may have on treatments for PD.
In summary, the involvement of PRL in the progression, diagnosis, and development of PD is not fully understood since plasma studies on PRL levels are inconclusive. Therefore, understanding the role of PRL in PD might be useful for the design of therapies to improve the quality of life of patients with PD.
6.3 Evidence of prolactin involvement in Huntington’s disease
Huntington’s disease (HD) also known as Huntington’s chorea is a chronic, progressive, neurodegenerative, and autosomal inherited disorder that severely affects the basal ganglia. HD is a consequence of an extension in a polymorphic trinucleotide repeat of cytosine-adenine-guanine, which is responsible for encoding glutamine. This abnormality is located in exon 1 of the N-terminal coding region of the huntingtin (HTT) [102, 103, 104].
The relationship between PRL and HD has been studied for many years [105]. One study showed that patients with HD have low basal and impaired PRL serum levels in response to both, chlorpromazine, and TRH. Another study analyzed basal concentrations of PRL in patients with HD
Conversely, medication-free patients with early-stage HD showed an insignificant increase in PRL serum levels [110]. This could be explained by the alterations in hypothalamic–pituitary dopamine signaling observed in HD and the loss of pituitary D2 receptor expression [111].
Moreover, PRL and other hormones were analyzed in HD and pre-manifest patients. Interestingly, significantly reduced PRL levels were reported in both pre-manifest and HD patients, suggesting that HD patients have an early dysfunction of the hypothalamic-pituitary system since changes in basal PRL levels are detectable early in pre-manifest HD subjects [112]. Concerning changes in PRL levels related to HD development, a study performed in stage II/III HD subjects
Finally, a recent meta-analysis aimed to highlight the possible relation between PRL serum levels and its role in ND development and demonstrated that patients with NDs, specifically in AD and PD, did not have significantly higher serum PRL levels compared with healthy controls; however, in patients with HD, serum PRL levels increased
7. The role of prolactin in neuroprotection in the hippocampus
Although few, there are reports indicating an important role of PRL in neuroprotection against excitotoxic damage, specifically in the hippocampus (a brain region that is widely affected due to its large number of glutamatergic receptors) [114, 115]. In postischemic lesions, PRL administration induced the expression of the glial fibrillary acidic protein, promoting astrogliosis [116]. Conversely, after inflicting hypoxic-ischemic injury in ischemia reperfusion by carotid artery occlusion rat model, increased PRLR mRNA and protein were observed in microglia 5 days after injury. This result suggests that PRL may have an important role in inducing astrocytosis [117]. This hints at the additional action that PRL may have in promoting the activation of astrocytes, which ultimately protect neurons. More research is required to elucidate the relation between PRL and astrocyte activation.
Interestingly, a similar protective function was noted after high-dose PRL was administered in rats in global cerebral ischemia induced by bilateral common carotid occlusion. PRL decreased cerebral infarction volume and edema associated with a significant reduction in neurotransmitters, particularly, gamma-aminobutyric acid, Glu, and calcium concentrations [118]. These observations suggest that PRL may restore both physiological and biochemical parameters in the damaged brain tissue. Hence, PRL is a promising molecule in the mitigation of cerebral ischemic damage.
As noted above, PRL mitigates neuronal damage caused by Glu- or KA-induced excitotoxicity, and interestingly, KA administration has been used extensively in rat models of epilepsy. Experiments using varying routes of KA administration, either by IP or ICV, and administering a single dose of PRL via IP, have shown protection of rat hippocampal neuronal density in CA1, CA, and CA4 areas [119, 120, 121]. These studies suggest that PRL confers neuroprotection against excitotoxicity by KA. Given that KA is a model of epilepsy, and that PRL mitigates neuronal damage by KA, it may be involved in the mitigation of diseases, such as epilepsy. However, further studies are needed to establish the key molecular mechanisms of PRL in the context of epilepsy. Finally, a recent study about the description of transcriptomic effects by PRL administration in the hippocampus of female rats revealed novel complex gene network interactions induced by PRL, with new functions, such as glial differentiation, axogenesis, synaptic transmission, postsynaptic potential, and neuronal and glial migration [15]. This evidence suggests that PRL is a hormone of interest in neuronal and protective processes.
In summary, prolactin, in addition to lactation, has more than 300 functions and has a significant involvement in the CNS, such as neurogenesis, remyelination, and particularly neuroprotection against excitotoxicity. Although little is known, signaling pathways, such as PI3K/AKT, induction of survival genes, and attenuation of intracellular calcium are the possible mechanisms to explain PRL-induced neuroprotection against excitotoxicity. This neuronal damage mechanism is observed in NDs. Interestingly, PRL plays an important role as a biomarker for some NDs but is also considered a promising molecule for diagnosis. Further, studies are needed to understand the regulation of PRL in NDs, as well as to explore the neuroprotective properties of PRL as a target to develop new treatments and therapies.
8. Conclusion
One of the main characteristics of NDs is excitotoxicity. Thus, it is necessary to further investigate the molecular mechanisms underlying excitotoxicity to prevent neuronal damage or death. Then, elucidating how molecules exert neuroprotective functions and identifying new molecules that exert neuroprotection is mandatory. Accordingly, in this chapter, we described PRL as an important tool to mitigate or prevent neuronal damage in NDs. The study of PRL and its role in NDs opens new avenues for the development of new therapy and treatment strategies for neuroprotection.
Acknowledgments
Gladys Molina-Salinas is a doctoral student from the Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM) and has received CONAHCYT fellowship 892106. This study was supported by grants from PAPIIT IN228420. Dr. Marco Cerbon received a financial support for sabbatical studies from PASPA-DGAPA UNAM.
Conflict of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the data reported in this chapter.
References
- 1.
Rodriguez-Chavez V, Moran J, Molina-Salinas G, et al. Participation of glutamatergic ionotropic receptors in Excitotoxicity: The neuroprotective role of prolactin. Neuroscience. 2021; 461 :180-193. DOI: 10.1016/j.neuroscience.2021.02.027 - 2.
Armada-Moreira A, Gomes JI, Pina CC, et al. Going the extra (synaptic) mile: Excitotoxicity as the road toward neurodegenerative diseases. Frontiers in Cellular Neuroscience. 2020; 14 :90. DOI: 10.3389/fncel.2020.00090 - 3.
Mehta A, Prabhakar M, Kumar P, et al. Excitotoxicity: Bridge to various triggers in neurodegenerative disorders. European Journal of Pharmacology. 2013; 698 :6-18. DOI: 10.1016/j.ejphar.2012.10.032 - 4.
Choi DW. Excitotoxicity: Still hammering the ischemic brain in 2020. Frontiers in Neuroscience. 2020; 14 :579953. DOI: 10.3389/fnins.2020.579953 - 5.
Avila J, Llorens-Martín M, Pallas-Bazarra N, et al. Cognitive decline in neuronal aging and Alzheimer’s disease: Role of NMDA receptors and associated proteins. Frontiers in Neuroscience. 2017; 11 :626. DOI: 10.3389/fnins.2017.00626 - 6.
Bano D, Ankarcrona M. Beyond the critical point: An overview of excitotoxicity, calcium overload and the downstream consequences. Neuroscience Letters. 2018; 663 :79-85. DOI: 10.1016/j.neulet.2017.08.048 - 7.
Lewerenz J, Maher P. Chronic glutamate toxicity in neurodegenerative diseases—What is the evidence? Frontiers in Neuroscience. 2015; 9 :1-20. DOI: 10.3389/fnins.2015.00469 - 8.
Brini M, Calì T, Ottolini D, et al. Neuronal calcium signaling: Function and dysfunction. Cellular and Molecular Life Sciences. 2014; 71 :2787-2814. DOI: 10.1007/s00018-013-1550-7 - 9.
Hara MR, Snyder SH. Cell signaling and neuronal death. Annual Review of Pharmacology and Toxicology. 2007; 47 :117-141. DOI: 10.1146/annurev.pharmtox.47.120505.105311 - 10.
Pluta R, Ułamek-Kozioł M, Czuczwar SJ. Neuroprotective and neurological/cognitive enhancement effects of curcumin after brain ischemia injury with alzheimer’s disease phenotype. International Journal of Molecular Sciences. 2018; 19 :1-16. DOI: 10.3390/ijms19124002 - 11.
Ambrogini P, Torquato P, Bartolini D, et al. Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease. 2019; 1865 :1098-1112. DOI: 10.1016/j.bbadis.2019.01.026 - 12.
Vanoye-Carlo A, Morales T, Ramos E, et al. Neuroprotective effects of lactation against kainic acid treatment in the dorsal hippocampus of the rat. Hormones and Behavior. 2008; 53 :112-123. DOI: 10.1016/j.yhbeh.2007.09.004 - 13.
Vergara-Castañeda E, Grattan DR, Pasantes-Morales H, et al. Prolactin mediates neuroprotection against excitotoxicity in primary cell cultures of hippocampal neurons via its receptor. Brain Research. 2016; 1636 :193-199. DOI: 10.1016/j.brainres.2016.02.011 - 14.
Rivero-Segura NA, Flores-Soto E, De La Cadena SG, et al. Prolactin-induced neuroprotection against glutamate excitotoxicity is mediated by the reduction of [Ca2+]i overload and NF-κB activation. PLoS One. 2017; 12 :1-16. DOI: 10.1371/journal.pone.0176910 - 15.
Cabrera-Reyes EA, Vanoye–Carlo A, Rodríguez-Dorantes M, et al. Transcriptomic analysis reveals new hippocampal gene networks induced by prolactin. Scientific Reports. 2019; 9 :1-12. DOI: 10.1038/s41598-019-50228-7 - 16.
Molina-Salinas G, Rivero-Segura NA, Cabrera-Reyes EA, et al. Decoding signaling pathways involved in prolactin-induced neuroprotection: A review. Frontiers in Neuroendocrinology. 2021; 61 :100913. DOI: 10.1016/j.yfrne.2021.100913 - 17.
Freeman ME, Kanyicska LA, Lerant A, et al. Prolactin: Structure , function , and regulation of secretion. American Physiological Society. 2000; 80 :1523-1631. DOI: 10.1152/physrev.2000.80.4.1523 - 18.
Cabrera-Reyes EA, Limón-Morales O, Rivero-Segura NA, et al. Prolactin function and putative expression in the brain. Endocrine. 2017; 57 :199-213. DOI: 10.1007/s12020-017-1346-x - 19.
Ben-Jonathan N, LaPensee CR, LaPensee EW. What can we learn from rodents about prolactin in humans? Endocrine Reviews. 2008; 29 :1-41. DOI: 10.1210/er.2007-0017 - 20.
Patil MJ, Henry MA, Akopian AN. Prolactin receptor in regulation of neuronal excitability and channels. Channels. 2014; 8 :193-202. DOI: 10.4161/chan.28946 - 21.
Bernard V, Young J, Chanson P, et al. New insights in prolactin: Pathological implications. Nature Reviews. Endocrinology. 2015; 11 :265-275. DOI: 10.1038/nrendo.2015.36 - 22.
Bernard V, Young J, Binart N. Prolactin—A pleiotropic factor in health and disease. Nature Reviews. Endocrinology. 2019; 15 :356-365. DOI: 10.1038/s41574-019-0194-6 - 23.
Grattan DR, Kokay IC. Prolactin: A pleiotropic neuroendocrine hormone. Journal of Neuroendocrinology. 2008; 20 :752-763. DOI: 10.1111/j.1365-2826.2008.01736.x - 24.
Binart N. Prolactin and pregnancy in mice and humans. Annales d’endocrinologie. 2016; 77 :126-127. DOI: 10.1016/j.ando.2016.04.008 - 25.
Marano RJ, Ben-Jonathan N. Minireview: Extrapituitary prolactin: An update on the distribution, regulation, and functions. Molecular Endocrinology. 2014; 28 :622-633. DOI: 10.1210/me.2013-1349 - 26.
Costanza M, Pedotti R. Prolactin: Friend or foe in central nervous system autoimmune inflammation? International Journal of Molecular Sciences. 2016; 17 :2012-2016. DOI: 10.3390/ijms17122026 - 27.
Costa-Brito AR, Gonçalves I, Santos CRA. The brain as a source and a target of prolactin in mammals. Neural Regeneration Research. 2022; 17 :1695-1702. DOI: 10.4103/1673-5374.332124 - 28.
Carretero J, Sánchez-Robledo V, Carretero-Hernández M, et al. Prolactin system in the hippocampus. Cell and Tissue Research. 2019; 375 :193-199. DOI: 10.1007/s00441-018-2858-2 - 29.
Gorvin CM. The prolactin receptor: Diverse and emerging roles in pathophysiology. Journal of Clinical & Translational Endocrinology. 2015; 2 :85-91. DOI: 10.1016/j.jcte.2015.05.001 - 30.
Molina-Salinas G, Rodríguez-Chávez V, Langley E, et al. Prolactin-induced neuroprotection against excitotoxicity is mediated via PI3K/AKT and GSK3β/NF-κB in primary cultures of hippocampal neurons. Peptides. 2023; 166 :171037. DOI: 10.1016/j.peptides.2023.171037 - 31.
Sangeeta Devi Y, Halperin J. Reproductive actions of prolactin mediated through short and long receptor isoforms. Molecular and Cellular Endocrinology. 2014; 382 :400-410. DOI: 10.1016/j.mce.2013.09.016 - 32.
Torner L, Neumann ID. The brain prolactin system: Involvement in stress response adaptations in lactation. Stress. 2002; 5 :249-257. DOI: 10.1080/1025389021000048638 - 33.
Horseman ND, Gregerson KA. Prolactin actions. Journal of Molecular Endocrinology. 2013; 19 :95-106. DOI: 10.1530/JME-13-0220 - 34.
Bole-Feysot C, Goffin V, Edery M, et al. Prolactin (PRL) and its receptor: Actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocrine Reviews. 1998; 19 :225-268. DOI: 10.1210/edrv.19.3.0334 - 35.
Borba VV, Zandman-Goddard G, Shoenfeld Y. Prolactin and autoimmunity: The hormone as an inflammatory cytokine. Best Practice & Research. Clinical Endocrinology & Metabolism. 2019; 33 :101324. DOI: 10.1016/j.beem.2019.101324 - 36.
Torner L. Actions of prolactin in the brain: From physiological adaptations to stress and neurogenesis to psychopathology. Frontiers in Endocrinology. 2016; 7 (25):1-6. DOI: 10.3389/fendo.2016.0002 - 37.
Larsen CM, Grattan DR. Prolactin-induced mitogenesis in the subventricular zone of the maternal brain during early pregnancy is essential for normal postpartum behavioral responses in the mother. Endocrinology. 2010; 151 :3805-3814. DOI: 10.1210/en.2009-1385 - 38.
Walker TL, Vukovic J, Koudijs MM, et al. Prolactin stimulates precursor cells in the adult mouse hippocampus. PLoS One. 2012; 7 :1-11. DOI: 10.1371/journal.pone.0044371 - 39.
Rivero-Segura NA, Coronado-Mares MI, Rincón-Heredia R, et al. Prolactin prevents mitochondrial dysfunction induced by glutamate excitotoxicity in hippocampal neurons. Neuroscience Letters. 2019; 701 :58-64. DOI: 10.1016/j.neulet.2019.02.027 - 40.
Olney JW, Price MT, Samson L, et al. The role of specific ions in glutamate neurotoxicity. Neuroscience Letters. 1986; 65 :65-71. DOI: 10.1016/0304-3940(86)90121-7 - 41.
Choi DW. Excitotoxic cell death. Journal of Neurobiology. 1992; 23 :1261-1276. DOI: 10.1002/neu.480230915 - 42.
Dong X, Wang Y, Qin Z. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacologica Sinica. 2009; 30 :379-387. DOI: 10.1038/aps.2009.24 - 43.
Reiner A, Levitz J. Glutamatergic signaling in the central nervous system: Ionotropic and metabotropic receptors in concert. Neuron. 2018; 98 :1080-1098. DOI: 10.1016/j.neuron.2018.05.018 - 44.
Hansen KB, Wollmuth LP, Bowie D, et al. Structure, function, and pharmacology of glutamate receptor ion channels. Pharmacological Reviews. 2021; 73 :298-487. DOI: 10.1124/pharmrev.120.000131 - 45.
Gross A, Katz SG. Non-apoptotic functions of BCL-2 family proteins. Cell Death and Differentiation. 2017; 24 :1348-1358. DOI: 10.1038/cdd.2017.22 - 46.
Zamani M, Hassanshahi J, Soleimani M, et al. Neuroprotective effect of olive oil in the hippocampus CA1 neurons following ischemia: Reperfusion in mice. Journal of Neurosciences in Rural Practice. 2013; 4 :164-170. DOI: 10.4103/0976-3147.112753 - 47.
Zheng X-Y, Zhang H-L, Luo Q , et al. Kainic acid-induced neurodegenerative model: Potentials and limitations. Journal of Biomedicine & Biotechnology. 2011; 2011 :457079. DOI: 10.1155/2011/457079 - 48.
Torner L, Karg S, Blume A, et al. Prolactin prevents chronic stress-induced decrease of adult hippocampal neurogenesis and promotes neuronal fate. The Journal of Neuroscience. 2009; 29 :1826-1833. DOI: 10.1523/JNEUROSCI.3178-08.2009 - 49.
Rodríguez-Chávez V, Flores-Soto E, Molina-Salinas G, et al. Prolactin reduces the kainic acid-induced increase in intracellular Ca2+ concentration, leading to neuroprotection of hippocampal neurons. Neuroscience Letters. 2023; 810 :137344. DOI: 10.1016/j.neulet.2023.137344 - 50.
Bredesen DE, Rao RV, Mehlen P. Cell death in the nervous system. Nature. 2006; 443 :796-802. DOI: 10.1038/nature05293 - 51.
Glass CK, Saijo K, Winner B, et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010; 140 :918-934. DOI: 10.1016/j.cell.2010.02.016 - 52.
Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nature Medicine. 2004; 10 :S10. DOI: 10.1038/nm1066 - 53.
Dutta RTB. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Progress in Neurobiology. 2011; 93 :1-12. DOI: 10.1016/j.pneurobio.2010.09.005 - 54.
Matías-Guiu JA, Oreja-Guevara C, Cabrera-Martín MN, et al. Amyloid proteins and their role in multiple sclerosis. Considerations in the use of amyloid-PET imaging. Frontiers in Neurology. 2016; 7 :1-7. DOI: 10.3389/fneur.2016.00053 - 55.
Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochemistry International. 2004; 45 :583-595. DOI: 10.1016/j.neuint.2004.03.007 - 56.
Kovacs GG. Molecular pathological classification of neurodegenerative diseases: Turning towards precision medicine. International Journal of Molecular Sciences. 2016; 17 :2-89. DOI: 10.3390/ijms17020189 - 57.
Kovacs GG. Concepts and classification of neurodegenerative diseases. Handbook of Clinical Neurology. 2017; 145 :301-307. DOI: 10.1016/B978-0-12-802395-2.00021-3 - 58.
Dugger BN, Dickson DW. Pathology of neurodegenerative diseases. Cold Spring Harbor Perspectives in Biology. 2017; 9 :1-22. DOI: 10.1101/cshperspect.a028035 - 59.
Hardy J, Duff K, Hardy KG, et al. Genetic dissection of Alzheimer’s disease and related dementias: Amyloid and its relationship to tau. Nature Neuroscience. 1998; 1 :355-358. DOI: 10.1038/1565 - 60.
Franceschi M, Perego L, Ferini-Strambi L, et al. Neuroendocrinological function in Alzheimer’s disease. Neuroendocrinology. 1988; 48 :367-370. DOI: 10.1159/000125036 - 61.
Duc Nguyen H, Pal YB, Hoang NHM, et al. Prolactin and its altered action in Alzheimer’s disease and Parkinson’s disease. Neuroendocrinology. 2022; 112 :427-445. DOI: 10.1159/000517798 - 62.
House A, Jones J. Increased response of serum prolactin to metoclopramide in senile dementia of Alzheimer type. International Journal of Geriatric Psychiatry. 1989; 4 :279-282. DOI: 10.1002/gps.930040506 - 63.
Bille A, Olafsson K, Jensen HV, et al. Prolactin responses to thyrotropin-releasing hormone in multi-infarct dementia and senile dementia of the Alzheimer type. Acta Psychiatrica Scandinavica. 1991; 83 :321-323. DOI: 10.1111/j.1600-0447.1991.tb05548.x - 64.
Pedrós I, Petrov D, Artiach G, et al. Adipokine pathways are altered in hippocampus of an experimental mouse model of Alzheimer’s disease. The Journal of Nutrition, Health & Aging. 2015; 19 :403-412. DOI: 10.1007/s12603-014-0574-5 - 65.
Kitagishi Y, Matsuda S. Diets involved in PPAR and PI3K/AKT/PTEN pathway may contribute to neuroprotection in a traumatic brain injury. Alzheimer’s Research and Therapy. 2013; 5 :1. DOI: 10.1186/alzrt208 - 66.
Matsuda S, Nakagawa Y, Tsuji A, et al. Implications of PI3K/AKT/PTEN signaling on superoxide Dismutases expression and in the pathogenesis of Alzheimer’s disease. Diseases. 2018; 6 :1-13. DOI: 10.3390/diseases6020028 - 67.
Plotnikov A, Li Y, Tran TH, et al. Oncogene-mediated inhibition of glycogen synthase kinase 3 beta impairs degradation of prolactin receptor. Cancer Research. 2008; 68 :1354-1361. DOI: 10.1158/0008-5472.CAN-07-6094 - 68.
Muñoz-Mayorga D, Guerra-Araiza C, Torner L, et al. Tau phosphorylation in female neurodegeneration: Role of estrogens, progesterone, and prolactin. Frontiers in Endocrinology. 2018; 9 :1-8. DOI: 10.3389/fendo.2018.00133 - 69.
Steinmetz D, Ramos E, Campbell SN, et al. Reproductive stage and modulation of stress-induced tau phosphorylation in female rats. Journal of Neuroendocrinology. 2015; 27 :827-834. DOI: 10.1111/jne.12323 - 70.
Grattan DR. The hypothalamo-prolactin axis. The Journal of Endocrinology. 2015; 226 :101-122. DOI: 10.1530/JOE-15-0213 - 71.
Dudas B, Merchenthaler I. Thyrotropin-releasing hormone axonal varicosities appear to innervate dopaminergic neurons in the human hypothalamus. Brain Structure & Function. 2020; 225 :2193-2201. DOI: 10.1007/s00429-020-02120-8 - 72.
Luo L, Stopa EG. Thyrotropin releasing hormone inhibits tau phosphorylation by dual signaling pathways in hippocampal neurons. Journal of Alzheimer’s Disease. 2004; 6 :527-536. DOI: 10.3233/jad-2004-6510 - 73.
van Osch LADM, Hogervorst E, Combrinck M, et al. Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease. Neurology. 2004; 62 :1967-1971. DOI: 10.1212/01.wnl.0000128134.84230.9f - 74.
Labudova O, Cairns N, Koeck T, et al. Thyroid stimulating hormone—Receptor overexpression in brain of patients with down syndrome and Alzheimer’s disease. Life Sciences. 1999; 64 :1037-1044. DOI: 10.1016/s0024-3205(99)00030-2 - 75.
Daimon CM, Chirdon P, Maudsley S, et al. The role of thyrotropin releasing hormone in aging and neurodegenerative diseases. American Journal of Alzheimer’s Disease (Columbia). 2013; 1 :10.7726. DOI: 10.7726/ajad.2013.1003 - 76.
Tan ZS, Beiser A, Vasan RS, et al. Thyroid function and the risk of Alzheimer disease: The Framingham study. Archives of Internal Medicine. 2008; 168 :1514-1520. DOI: 10.1001/archinte.168.14.1514 - 77.
Zetterberg H, Bendlin BB. Biomarkers for Alzheimer’s disease—Preparing for a new era of disease-modifying therapies. Molecular Psychiatry. 2021; 26 :296-308. DOI: 10.1038/s41380-020-0721-9 - 78.
Leung YY, Toledo JB, Nefedov A, et al. Identifying amyloid pathology-related cerebrospinal fluid biomarkers for Alzheimer’s disease in a multicohort study. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2015; 1 :339-348. DOI: 10.1016/j.dadm.2015.06.008 - 79.
Zverova M, Kitzlerova E, Fisar Z, et al. Interplay between the APOE genotype and possible plasma biomarkers in Alzheimer’s disease. Current Alzheimer Research. 2018; 15 :938-950. DOI: 10.2174/1567205015666180601090533 - 80.
Tariot PN, Upadhyaya A, Sunderland T, et al. Physiologic and neuroendocrine responses to intravenous naloxone in subjects with Alzheimer’s disease and age-matched controls. Biological Psychiatry. 1999; 46 :412-419. DOI: 10.1016/s0006-3223(98)00329-1 - 81.
Beama CR, Kaneshiro C, Jang JY, Reynolds CA, Pedersen NL, Gatz M. Differences between women and men in incidence rates of dementia and Alzheimer’s disease. Journal of Alzheimer’s Disease. 2018; 64 :1077-1083. DOI: 10.3233/JAD-180141 - 82.
Riedel O, Bitters D, Amann U, et al. Estimating the prevalence of Parkinson’s disease (PD) and proportions of patients with associated dementia and depression among the older adults based on secondary claims data. International Journal of Geriatric Psychiatry. 2016; 31 :938-943. DOI: 10.1002/gps.4414 - 83.
Nitkowska M, Tomasiuk R, Czyzyk M, et al. Prolactin and sex hormones levels in males with Parkinson’s disease. Acta Neurologica Scandinavica. 2015; 131 :411-416. DOI: 10.1111/ane.12334 - 84.
Matilla-Dueñas A, Corral-Juan M, Rodríguez-Palmero Seuma A, et al. Rare neurodegenerative diseases: Clinical and genetic update. Advances in experimental medicine and biology. Advances in Experimental Medicine and Biology. 2017; 1031 :443-496. DOI: 10.1007/978-3-319-67144-4_25 - 85.
Heller J, Dogan I, Schulz JB, et al. Evidence for gender differences in cognition, emotion and quality of life in Parkinson’s disease? Aging and Disease. 2014; 5 :63-75. DOI: 10.14366/AD.2014.050063 - 86.
Hayes MT. Parkinson’s disease and parkinsonism. The American Journal of Medicine. 2019; 132 :802-807. DOI: 10.1016/j.amjmed.2019.03.001 - 87.
Cerri S, Mus L, Blandini F. Parkinson’s disease in women and men: What’s the difference? Journal of Parkinson’s Disease. 2019; 9 :501-515. DOI: 10.3233/JPD-191683 - 88.
Solla P, Cannas A, Ibba FC, et al. Gender differences in motor and non-motor symptoms among Sardinian patients with Parkinson’s disease. Journal of the Neurological Sciences. 2012; 323 :33-39. DOI: 10.1016/j.jns.2012.07.026 - 89.
Liu B, Dluzen DE. Oestrogen and nigrostriatal dopaminergic neurodegeneration: Animal models and clinical reports of Parkinson’s disease. Clinical and Experimental Pharmacology & Physiology. 2007; 34 :555-565. DOI: 10.1111/j.1440-1681.2007.04616.x - 90.
Saunders-Pullman R, Gordon-Elliott J, Parides M, et al. The effect of estrogen replacement on early Parkinson’s disease. Neurology. 1999; 52 :1417-1421. DOI: 10.1212/wnl.52.7.1417 DOI: 10.1212/wnl.52.7.1417 - 91.
Członkowska A, Ciesielska A, Gromadzka G, et al. Gender differences in neurological disease: Role of estrogens and cytokines. Endocrine. 2006; 29 :243-256. DOI: 10.1385/ENDO:29:2:243 - 92.
Gustafson P, Kokay I, Sapsford T, et al. Prolactin regulation of the HPA axis is not mediated by a direct action upon CRH neurons: Evidence from the rat and mouse. Brain Structure & Function. 2017; 222 :3191-3204. DOI: 10.1007/s00429-017-1395-1 - 93.
Eisler T, Thorner MO, MacLeod RM, et al. Prolactin secretion in Parkinson disease. Neurology. 1981; 31 :1356-1359. DOI: 10.1212/wnl.31.10.1356 - 94.
Murri L, Iudice A, Muratorio A, et al. Spontaneous nocturnal plasma prolactin and growth hormone secretion in patients with Parkinson’s disease and Huntington’s chorea. European Neurology. 1980; 19 :198-206. DOI: 10.1159/000115147 - 95.
Kostić VS, Lecić D, Doder M, et al. Prolactin and cortisol responses to fenfluramine in Parkinson’s disease. Biological Psychiatry. 1996; 40 :769-775. DOI: 10.1016/0006-3223(95)00496-3 - 96.
Martinez-Campos A, Giovannini P, Parati E, et al. Growth hormone and prolactin stimulation by Madopar in Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry. 1981; 44 :1116-1123. DOI: 10.1136/jnnp.44.12.1116 - 97.
Karayel O, Virreira Winter S, Padmanabhan S, et al. Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease. Cell Reports Medicine. 2022; 3 :100661. DOI: 10.1016/j.xcrm.2022.100661 - 98.
Winkler AS, Landau S, Chaudhuri KR. Serum prolactin levels in Parkinson’s disease and multiple system atrophy. Clinical Autonomic Research. 2002; 12 :393-398. DOI: 10.1007/s10286-002-0025-y - 99.
Zorovic M, Kolmančič K, Živin M. Effects of L-dopa on expression of prolactin and synaptotagmin IV in 17-beta-estradiol-induced prolactinomas of ovariectomized hemiparkinsonian rats. Bosnian Journal of Basic Medical Sciences. 2021; 21 :702-711. DOI: 10.17305/bjbms.2021.5491 - 100.
Kasuya E, Yayou K, Sutoh M. L-DOPA attenuates prolactin secretion in response to isolation stress in Holstein steers. Animal Science Journal. 2013; 84 :562-568. DOI: 10.1111/asj.12037 - 101.
Cacabelos R. Parkinson’s disease: From pathogenesis to pharmacogenomics. International Journal of Molecular Sciences. 2017; 18 :533-551. DOI: 10.3390/ijms18030551 - 102.
Müller T. Investigational agents for the management of Huntington’s disease. Expert Opinion on Investigational Drugs. 2017; 26 :175-185. DOI: 10.1080/13543784.2017.1270266 - 103.
Paulsen JS, Long JD, Ross CA, et al. Prediction of manifest Huntington’s disease with clinical and imaging measures: A prospective observational study. Lancet Neurology. 2014; 13 :1193-1201. DOI: 10.1016/S1474-4422(14)70238-8 - 104.
Kim A, Lalonde K, Truesdell A, et al. New avenues for the treatment of Huntington’s disease. International Journal of Molecular Sciences. 2021; 22 :8363. DOI: 10.3390/ijms22168363 - 105.
Hayden MR, Vinik AI, Paul M, et al. Impaired prolactin release in Huntington’s chorea. Evidence for dopaminergic excess. Lancet. 1977; 2 :423-426. DOI: 10.1016/s0140-6736(77)90608-0 - 106.
Chalmers RJ, Johnson RH, Keogh HJ, et al. Growth hormone and prolactin response to bromocriptine in patients with Huntington’s chorea. Journal of Neurology, Neurosurgery, and Psychiatry. 1978; 41 :135-139. DOI: 10.1136/jnnp.41.2.135 - 107.
Durso R, Tamminga CA, Ruggeri S, et al. Twenty-four hour plasma levels of growth hormone and prolactin in Huntington’s disease. Journal of Neurology, Neurosurgery, and Psychiatry. 1983; 46 :1134-1137. DOI: 10.1136/jnnp.46.12.1134 - 108.
Durso R, Tamminga CA, Denaro A, et al. Plasma growth hormone and prolactin response to dopaminergic GABAmimetic and cholinergic stimulation in Huntington’s disease. Neurology. 1983; 33 :1229-1232. DOI: 10.1212/wnl.33.9.1299 - 109.
Duc Nguyen H, Hoang NMH, Ko M, et al. Association between serum prolactin levels and neurodegenerative diseases: Systematic review and meta-analysis. Neuroimmunomodulation. 2022; 29 :85-96. DOI: 10.1159/000519552 - 110.
Aziz NA, Pijl H, Frölich M, et al. Altered thyrotropic and lactotropic axes regulation in Huntington’s disease. Clinical Endocrinology. 2010; 73 :540-545. DOI: 10.1111/j.1365-2265.2010.03836.x - 111.
Björkqvist M, Petersén A, Bacos K, et al. Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington’s disease. Human Molecular Genetics. 2006; 15 :1713-1721. DOI: 10.1093/hmg/ddl094 - 112.
Wang R, Ross CA, Cai H, et al. Metabolic and hormonal signatures in pre-manifest and manifest Huntington’s disease patients. Frontiers in Physiology. 2014; 5 :231. DOI: 10.3389/fphys.2014.00231 - 113.
Kalliolia E, Silajdžić E, Nambron R, et al. A 24-hour study of the Hypothalamo-pituitary axes in Huntington’s disease. PLoS One. 2015; 10 :e0138848. DOI: 10.1371/journal.pone.0138848 - 114.
Baude A, Nusser Z, Molnar E, et al. High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus. Neuroscience. 1995; 69 :1031-1055. DOI: 10.1016/0306-4522(95)00350-r - 115.
Wenk GL, Barnes CA. Regional changes in the hippocampal density of AMPA and NMDA receptors across the lifespan of the rat. Brain Research. 2000; 885 :1-5. DOI: 10.1016/s0006-8993(00)02792-x - 116.
Anagnostou I, Reyes-Mendoza J, Morales T. Glial cells as mediators of protective actions of prolactin (PRL) in the CNS. General and Comparative Endocrinology. 2018; 265 :106-110. DOI: 10.1016/j.ygcen.2018.01.024 - 117.
Möderscheim TAE, Gorba T, Pathipati P, et al. Prolactin is involved in glial responses following a focal injury to the juvenile rat brain. Neuroscience. 2007; 145 :963-973. DOI: 10.1016/j.neuroscience.2006.12.053 - 118.
Vermani B, Mukherjee S, Kumar G, et al. Prolactin attenuates global cerebral ischemic injury in rat model by conferring neuroprotection. Brain Injury. 2020; 34 :685-693. DOI: 10.1080/02699052.2020.1726466 - 119.
Cabrera V, Cantú D, Ramos E, et al. Lactation is a natural model of hippocampus neuroprotection against excitotoxicity. Neuroscience Letters. 2009; 461 :136-139. DOI: 10.1016/j.neulet.2009.06.017 - 120.
Tejadilla D, Cerbón M, Morales T. Prolactin reduces the damaging effects of excitotoxicity in the dorsal hippocampus of the female rat independently of ovarian hormones. Neuroscience. 2010; 169 :1178-1185. DOI: 10.1016/j.neuroscience.2010.05.074 - 121.
Ortiz-Pérez A, Limón-Morales O, Rojas-Castañeda JC, et al. Prolactin prevents the kainic acid-induced neuronal loss in the rat hippocampus by inducing prolactin receptor and putatively increasing the VGLUT1 overexpression. Neuroscience Letters. 2019; 694 :116-123. DOI: 10.1016/j.neulet.2018.11.052