Current Drugs Strategies for Treatment of Rare Neurodegenerative Diseases

Abstract

Nervous system problems affect around 600 million people worldwide. Among these, neurodegenerative illnesses are often distinguished by a late adult start, a progressive clinical course, and a localized loss of neurons in the central nervous system. These include, among others, multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), Huntington’s disease, Prion diseases, encephalitis, epilepsy, genetic brain disorders, hydrocephalus, stroke, and Alzheimer’s and other less common dementias. The brain stem, cerebellum, thalamus, hypothalamus, basal ganglia, cerebral cortex, and intracranial white matter are among the areas that neurodegeneration typically affects. Mendelian inheritance is well-established, despite the fact that most neurodegenerative illnesses are sporadic. The neuropathological findings and clinical symptoms in hereditary neurodegenerative disorders are intriguing. Regretfully, there are few neurodegenerative diseases for which no effective treatments are available. The rare hereditary types of neurodegenerative diseases, such as ataxias, multiple system atrophy, spastic paraplegias, Parkinson’s disease, dementias, motor neuron diseases, and uncommon metabolic disorders, are highlighted in this chapter along with their clinical and genetic characteristics.

1. Introduction

Rare neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of the structure and function of the nervous system. These conditions are considered rare because they affect a small number of individuals in comparison to more common neurodegenerative diseases like Alzheimer’s or Parkinson’s. Many of these diseases are genetic in nature, resulting from mutations in specific genes. Here are some examples and basics about neurodegenerative diseases.

Neurodegenerative diseases are a subset of degenerative diseases that primarily affect the structure and function of the nervous system, leading to the progressive degeneration of neurons. These conditions often result in cognitive decline, motor dysfunction, and, in many cases, a reduced quality of life. Here are some examples and basics about neurodegenerative diseases [1, 2]:

1. Common neurodegenerative diseases

   • Alzheimer’s disease (AD): It affects memory, thinking, and behavior. It is the most common cause of dementia.

   • Parkinson’s disease (PD): It involves the malfunction and death of certain nerve cells in the brain, leading to movement-related symptoms.

   • Huntington’s disease (HD): It is a genetic disorder that causes the progressive breakdown of nerve cells in the brain, leading to motor and cognitive impairments.

   • Amyotrophic lateral sclerosis (ALS): It affects nerve cells in the brain and spinal cord, leading to the loss of voluntary muscle control [1, 2].

2. Common features

   • Progressive degeneration: Neurodegenerative diseases are characterized by the gradual and irreversible loss of neurons and their function.

   • Accumulation of abnormal proteins: Many neurodegenerative diseases are associated with the buildup of abnormal protein that aggregates in the brain, such as beta-amyloid plaques in AD or Lewy bodies PD.

   • Inflammation: Neuroinflammation is often present, contributing to the progression of the disease [1, 2].

3. Symptoms

   • Symptoms vary depending on the specific disease but may include memory loss, cognitive decline, tremors, muscle stiffness, difficulty with movement and coordination, and changes in mood or behavior.

   • As the diseases progress, individuals may experience worsening symptoms and a decline in overall functioning [1, 2].

4. Causes

   • While the exact causes of neurodegenerative diseases are often complex and not fully understood, genetic factors, environmental influences, and the accumulation of abnormal proteins are commonly implicated.

   • Some neurodegenerative diseases have a genetic component, with mutations in specific genes increasing the risk of developing the condition [1, 2].

5. Diagnosis

   • Diagnosis involves a thorough medical history, neurological examinations, cognitive assessments, and often imaging studies (MRI, CT scans) to detect structural changes in the brain.

   • In some cases, genetic testing may be employed to identify specific mutations associated with familial forms of the diseases [1, 2].

6. Treatment

   • Most neurodegenerative diseases have no cure, however, treatment focuses on managing symptoms and improving the individual’s quality of life.

   • Medications, physical therapy, occupational therapy, and supportive care are common approaches [1, 2].

7. Research and advances

   • Ongoing research aims to understand the underlying mechanisms of neurodegenerative diseases, identify potential biomarkers, and develop novel therapeutic strategies.

   • Clinical trials explore new medications, gene therapies, and interventions aimed at slowing or halting disease progression.

It is important to note that the field of neurodegenerative diseases is rapidly evolving, and ongoing research is critical for advancing our understanding and developing effective treatments.

Rare neurodegenerative diseases, also known as rare neurologic disorders, are a diverse group of conditions that affect the nervous system and are characterized by progressive degeneration. These diseases are considered rare because they affect a small number of individuals within the population. While each rare neurodegenerative disease is unique, there are some common features and considerations [1, 2]:

1. Limited prevalence

   • Rare neurodegenerative diseases are defined by their low prevalence, often affecting a small number of people within a population.

   • The rarity of these conditions can pose challenges for diagnosis, research, and the development of treatments due to limited awareness and resources [1, 2].

2. Heterogeneity

   • There is a significant heterogeneity among rare neurodegenerative diseases. Each disorder has distinct clinical features, genetic underpinnings, and disease progression.

   • Some examples of rare neurodegenerative diseases include Niemann-Pick disease, Batten disease, Ataxia-telangiectasia, and various forms of leukodystrophies [1, 2].

3. Genetic basis

   • Many rare neurodegenerative diseases have a genetic component, resulting from mutations in specific genes.

   • In some cases, these conditions follow an autosomal recessive, autosomal dominant, or X-linked inheritance pattern [3].

4. Early onset

   • Some rare neurodegenerative diseases manifest early in life, often during childhood or adolescence.

   • Early-onset forms may present unique challenges in terms of diagnosis, management, and the impact on the affected individuals and their families [3].

5. Multisystem involvement

   • Several rare neurodegenerative diseases involve multiple organ systems, not just the nervous system. This can lead to a wide range of symptoms and complications.

   • Examples include disorders affecting the nervous system, muscles, metabolism, and other organs [3].

6. Diagnostic challenges

   • Diagnosing rare neurodegenerative diseases can be challenging due to their low prevalence, the diversity of symptoms, and limited awareness among healthcare professionals.

   • Genetic testing and advanced imaging techniques may be crucial for accurate diagnosis [3].

7. Limited treatment options

   • Due to the rarity and often poorly understood nature of these diseases, treatment options are limited, and there may be no cure.

   • Management typically focuses on alleviating symptoms, providing supportive care, and improving the individual’s quality of life [3].

8. Research and collaboration

   • Ongoing research efforts aim to understand the genetic basis, underlying mechanisms, and potential therapeutic targets for rare neurodegenerative diseases.

   • Collaboration between researchers, clinicians, and patient advocacy groups is essential for advancing knowledge and developing treatments.

Given the rarity and complexity of these diseases, specialized clinics and research centers often play a crucial role in the diagnosis, management, and research efforts related to rare neurodegenerative diseases.

These diseases pose significant challenges for both patients and their families due to their rarity, limited treatment options, and often rapid progression. Research efforts are ongoing to better understand the underlying mechanisms and develop potential therapies for these conditions [3, 4].

2. Pathogenesis of Alzheimer’s disease (AD)

The pathogenesis of AD is complex and involves multiple factors, including genetic, environmental, and molecular contributors. While the exact mechanisms are not fully understood, several key features are associated with the development and progression of AD [5]:

1. Amyloid beta (Aβ) accumulation

   • One of the hallmarks of AD is the accumulation of abnormal protein aggregates called beta-amyloid plaques in the brain.

   • Aβ is a protein fragment derived from the larger amyloid precursor protein (APP). In AD, there is an imbalance in the production and clearance of Aβ, leading to its accumulation in the brain [6].

2. Tau protein pathology

   • Tau is a protein that plays a crucial role in maintaining the structural integrity of neurons by stabilizing microtubules.

   • In AD, abnormal modifications of tau lead to the formation of neurofibrillary tangles inside neurons. These tangles disrupt the normal functioning of neurons and contribute to their degeneration [7].

3. Neuroinflammation

   • Chronic inflammation in the brain is associated with the progression of AD. Immune cells, such as microglia, become activated and contribute to the inflammatory response.

   • Inflammation may exacerbate the accumulation of Aβ and tau pathology and contribute to neuronal damage [7].

4. Genetic factors

   • While most cases of AD are sporadic, a small percentage is associated with specific genetic mutations. Mutations in genes such as APP, PSEN1, and PSEN2 are linked to familial forms of AD.

   • These genes are involved in the production and processing of Aβ [3, 5].

5. Mitochondrial dysfunction

   • Impaired mitochondrial function has been observed in AD. Mitochondria play a crucial role in energy production and maintenance of cellular health.

   • Dysfunction in mitochondria may contribute to increased oxidative stress and damage to neurons [3, 5].

6. Synaptic dysfunction and neuronal loss

   • Synaptic dysfunction occurs early in the course of AD, leading to impaired communication between neurons.

   • Progressive neuronal loss, particularly in regions critical for memory and cognitive function, is a characteristic feature of AD [3, 5].

7. Vascular factors

   • Vascular risk factors, such as hypertension and atherosclerosis, have been associated with an increased risk of developing AD.

   • Vascular dysfunction may contribute to decreased blood flow and nutrient supply to the brain, impacting neuronal health [3, 5].

8. Environmental and lifestyle factors

   • Several environmental factors, such as education, diet, physical activity, and social engagement, may influence the risk of developing AD.

   • Chronic stress, traumatic brain injury, and exposure to certain toxins have also been studied in relation to AD risk.

The interaction and interplay of these factors likely contribute to the complex pathogenesis of AD. Research is ongoing to better understand these mechanisms, and potential therapeutic strategies are being explored to target various aspects of the disease process. Early diagnosis and intervention remain important areas of focus for improving outcomes and developing effective treatments for AD [3, 5].

3. Pathogenesis of Parkinson’s disease (PD)

PD is a neurodegenerative disorder characterized by the progressive degeneration of dopamine-producing neurons in the brain. The exact cause of PD is not fully understood, and it likely involves a combination of genetic and environmental factors. Here are key aspects of the pathogenesis of PD [5].

1. Dopaminergic neuron degeneration

   • PD primarily affects a region of the brain called the substantia nigra, where dopaminergic neurons are located. These neurons are responsible for producing dopamine, a neurotransmitter crucial for motor control and coordination.

   • Progressive degeneration of these dopaminergic neurons leads to a reduction in dopamine levels, resulting in the motor symptoms characteristic of PD [3, 5].

2. Alpha-synuclein accumulation

   • The abnormal accumulation of a protein called alpha-synuclein in the form of Lewy bodies is a pathological hallmark of PD.

   • These aggregated proteins are believed to interfere with normal cellular function and contribute to the degeneration of dopaminergic neurons [3, 5].

3. Mitochondrial dysfunction

   • Mitochondria, the cellular organelles responsible for energy production, play a role in the pathogenesis of PD.

   • Dysfunction in mitochondrial activity, including oxidative stress and impaired energy metabolism, may contribute to neuronal damage and cell death [3, 5].

4. Genetic factors

   • While most cases of PD are sporadic, a small percentage is associated with specific genetic mutations. Mutations in genes such as SNCA (encoding alpha-synuclein), LRRK2, PARK2, and PINK1 have been linked to familial forms of PD.

   • Genetic factors can influence the susceptibility to PD and may contribute to its pathogenesis [3, 5].

5. Oxidative stress

   • Increased oxidative stress, resulting from an imbalance between the production of reactive oxygen species (ROS) and the ability of cells to neutralize them, is implicated in PD.

   • Oxidative stress can damage cellular structures, including proteins, lipids, and DNA, leading to neuronal dysfunction and death [3, 5].

6. Inflammation

   • Neuroinflammation, involving the activation of microglia and other immune cells in the brain, is associated with PD.

   • Inflammatory processes may contribute to the degeneration of dopaminergic neurons and the progression of the disease [3, 5].

7. Environmental factors

   • Exposure to certain environmental toxins has been implicated in the development of PD. For example, pesticides, herbicides, and industrial chemicals may contribute to an increased risk.

   • Traumatic brain injury and viral infections have also been suggested as potential environmental triggers [3, 5].

8. Autophagy dysfunction

   • Autophagy, a cellular process responsible for removing damaged or dysfunctional cellular components, is impaired in PD.

   • Dysregulation of autophagy may contribute to the accumulation of alpha-synuclein and other cellular abnormalities.

Understanding the multifaceted nature of PD pathogenesis is essential for the development of targeted therapies. Research efforts continue to investigate these mechanisms and identify potential interventions to slow or halt the progression of the disease. Early diagnosis, symptomatic management, and ongoing research are critical components of PD care [7, 8].

4. Pathogenesis of Huntington’s disease (HD)

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the HTT gene, leading to the production of an abnormal form of the huntingtin protein. The pathogenesis of HD involves a range of cellular and molecular mechanisms that result in progressive damage to specific areas of the brain. Here are key aspects of the pathogenesis of HD [5]:

1. Genetic mutation

   • HD is caused by an expanded CAG repeat sequence in the HTT gene. The CAG repeat leads to an abnormally long polyglutamine stretch in the huntingtin protein.

   • Individuals with a higher number of CAG repeats tend to exhibit an earlier onset and more severe symptoms [3, 5].

2. Mutant huntingtin protein aggregation

   • The mutant huntingtin protein has a tendency to misfold and aggregate, forming insoluble clumps within neurons. These aggregates are known as inclusion bodies.

   • The accumulation of these aggregates is believed to interfere with normal cellular function and contribute to neuronal dysfunction and death [9].

3. Neuronal degeneration

   • The regions of the brain most affected by HD include the striatum (especially the caudate nucleus and putamen), cerebral cortex, and other subcortical structures.

   • Progressive degeneration of neurons in these brain regions, particularly GABAergic medium spiny neurons in the striatum, is a characteristic feature of the disease [7].

4. Excitotoxicity

   • Dysregulation of neurotransmitters, particularly excessive release of glutamate, may lead to excitotoxicity. Excessive glutamate can overstimulate neurons, causing damage and cell death.

   • The imbalance in neurotransmitter signaling contributes to the neurodegenerative process [7].

5. Mitochondrial dysfunction

   • HD is associated with mitochondrial dysfunction, including impaired energy production and increased oxidative stress.

   • Dysfunctional mitochondria may contribute to neuronal damage, especially in regions with high energy demands [3, 5].

6. Impaired axonal transport

   • The mutant huntingtin protein disrupts the normal intracellular transport of various cellular components, including vesicles and organelles, along neuronal axons.

   • Impaired axonal transport contributes to the dysfunction of neuronal processes and the accumulation of toxic substances [7].

7. Transcriptional dysregulation

   • Mutant huntingtin affects gene transcription, leading to alterations in the expression of various genes involved in neuronal function and survival.

   • Transcriptional dysregulation contributes to the overall disruption of cellular processes in HD [9].

8. Autophagy impairment

   • Autophagy, a cellular process responsible for clearing damaged or dysfunctional cellular components, is impaired in HD.

   • Dysfunction in autophagy contributes to the accumulation of mutant huntingtin protein and other cellular abnormalities.

Understanding the intricate details of HD pathogenesis is crucial for developing targeted therapies. While there is currently no cure for HD, ongoing research aims to identify potential interventions that could modify the course of the disease or alleviate symptoms. Genetic testing and counseling are important components of managing the risk of HD within families [7].

5. Pathogenesis of amyotrophic lateral sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord. The pathogenesis of ALS is complex and involves a combination of genetic and environmental factors. Here are key aspects of the pathogenesis of ALS [10]:

1. Motor neuron degeneration

   • ALS is characterized by the selective degeneration of both upper motor neurons (located in the brain) and lower motor neurons (located in the spinal cord and brainstem).

   • The loss of these motor neurons disrupts the communication between the brain and muscles, leading to muscle weakness, atrophy, and eventually paralysis [7].

2. Genetic factors

   • Approximately 5–10% of ALS cases are considered familial, meaning they have a clear genetic component. Mutations in several genes have been associated with familial ALS, including:

     • C9orf72: The most common genetic cause of familial ALS.

     • SOD1 (superoxide dismutase 1): Mutations in this gene are associated with a significant proportion of familial ALS cases.

     • TARDBP (TDP-43): Abnormalities in the TDP-43 protein are found in both familial and sporadic ALS cases [3, 5].

3. Protein aggregation

   • Misfolded and aggregated proteins, including TDP-43 and FUS, are found in the cytoplasm of affected motor neurons in many ALS cases.

   • These protein aggregates may disrupt normal cellular function and contribute to neurodegeneration.

4. Excitotoxicity

   • Dysregulation of glutamate, a neurotransmitter, can lead to excitotoxicity, where excessive glutamate signaling causes damage to motor neurons.

   • Glutamate-mediated excitotoxicity is thought to play a role in the selective vulnerability of motor neurons in ALS [9, 10].

5. Mitochondrial dysfunction

   • Impaired mitochondrial function and energy metabolism have been implicated in ALS.

   • Mitochondrial dysfunction may contribute to oxidative stress, a process that damages cells through the production of reactive oxygen species [3, 5].

6. Oxidative stress

   • Elevated levels of oxidative stress, resulting from an imbalance between the production of reactive oxygen species and the body’s ability to neutralize them, are observed in ALS.

   • Oxidative stress contributes to cellular damage and may be involved in the death of motor neurons [3, 5].

7. Glia involvement

   • Glial cells, including astrocytes and microglia, play a role in ALS pathology. Dysfunction in these support cells can contribute to neuroinflammation and the progression of the disease.

   • The activation of astrocytes and microglia may contribute to the release of inflammatory molecules and the removal of damaged neurons [3, 7].

8. RNA processing abnormalities

   • Disruptions in RNA processing and transport have been implicated in ALS pathogenesis.

   • Mutations in genes like C9orf72 can lead to abnormal RNA processing, affecting the function of motor neurons [3, 7].

9. Neuroinflammation

   • Activation of the immune system within the central nervous system contributes to neuroinflammation in ALS.

   • Inflammatory processes involving microglia and astrocytes may exacerbate neuronal damage and accelerate disease progression [7].

Understanding the underlying mechanisms of ALS is crucial for developing effective therapies. While there is currently no cure for ALS, research is ongoing to identify potential targets for intervention and improve the management of the disease. Multidisciplinary care, supportive therapies, and assistive devices are currently used to enhance the quality of life for individuals living with ALS [8, 11, 12].

Although rare neurodegenerative diseases are particularly challenging for both research and drug development, encouraging progress has been made in the development of drugs for many of these diseases.

6. Amyotrophic lateral sclerosis (ALS)

So far, only four drugs have been used, Riluzole (an antiglutamatergic drug), dextromethorphan hydrobromide and quinidine sulfate (DHQ) (a non-competitive NMDA receptor antagonist), edaravone (an antioxidant drug), and sodium phenylbutyrate and Taurursodiol (PB/TUDCA) is a cellular stress signaling blocker approved by the FDA for ALS [13].

6.1 Current treatment options

6.1.1 Riluzole

Riluzole is the only treatment available for people with ALS. The goal is to reduce excitotoxicity, specifically glutamate. Riluzole was approved by the FDA in 1995 and then by the EMA in 1996. Riluzole is an effective drug and side effects such as fatigue, nausea, stomach problems, and elevation of intestinal and liver enzymes have been detected [14].

6.1.2 Edaravone

Following the approval of Riluzole, no new drugs entered the market for several years until edaravone was approved in Japan and South Korea in 2015. FDA approval in 2017 was followed by the Chinese NMPA and Switzerland, followed by entry in 2019, Indonesia in 2020, and finally Malaysia and Thailand in 2021. Edaravone has been used for many years in Japan for stroke prevention, reducing oxidative depression and neuroinflammation by eliminating free radicals. Common side effects of edaravone treatment are bruising, gait disturbance, headache, and skin irritation [15].

To date, the dose of edavalone is 60 mg/day. Once the first dose was given for a period of 14 days, it was given for 10 days each subsequent month. However, this treatment is less suitable than oral medication. A total of 105 mg/day oral suspension will be approved by the FDA in 2022. Meanwhile, Ferrer (TRICALS) is conducting a Phase III trial evaluating the safety and effectiveness of FNP122, another oral form of edaravone [15].

6.1.3 Sodium phenylbutyrate and taurursodiol

Recently, sodium phenylbutyrate and Taurursodiol (also known as PB-TURSO or PB-TUDCA) have been introduced in a combination. The drug is currently approved by the FDA and Canada, both of which have previously been approved for medical use. Both have been identified as inhibitors of neuronal apoptosis, and their synergistic effects are thought to reduce cell death and oxidative stress by reducing endoplasmic reticulum (ER) stress and mitochondrial dysfunction [15].

The most common side effects in the Phase II trial were diarrhea, abdominal pain, nausea, and upper respiratory tract infection. Gastrointestinal tract-related adverse events occur more frequently in the first 3 weeks of treatment [13].

Sodium phenylbutyrate/ Taurursodiol is formulated as an oral suspension and powder to be mixed with hot water. The dose is 3 g of sodium phenylbutyrate and 1 g of Taurursodiol; start taking it once a day for 3 weeks, then twice a day [15].

6.1.4 Anakinra and Fingolimod

Arterial inflammation is now recognized as a possible pathology in ALS. Therefore, inhibitors of neuroinflammatory pathways may be helpful [16].

Anakinra is an IL-1 receptor inhibitor whose protective effects have been studied in experimental and clinical studies. Anakinra has been shown to extend life expectancy in SOD1-G93A mice [17].

Additionally, Fingolimod (Gilenya) acts as an anti-inflammatory drug by inhibiting lymphocyte influx from lymphoid tissue and reducing circulating lymphocytes associated with sphingosine-1-phosphate receptor (S1PR) inhibition. Experimental studies in SOD1-G93A mice showed that fingolimod improved survival. In addition to its effects in multiple sclerosis (MS), fingolimod is a safe and tolerable drug in ALS patients. Side effects include bradycardia at the initial dose, mild decrease in FEV1, macular edema, and progressive multifocal leukoencephalopathy [18].

6.1.5 Masitinib

Masitinib is a selective tyrosine kinase inhibitor that exerts neuroprotective effects by modulating the immune system and microglia activity [19].

Masitinib is a selective tyrosine kinase inhibitor and is unique compared to other ALS drugs in targeting the immune system in the central and peripheral nervous system, including microglia, macrophages, and mast cells. It is used orally and has antitumor, neuroprotective and anti-inflammatory activities. It regulates mast cell survival, migration, and degranulation by inhibiting important growth and differentiation pathways (and indirectly regulating various proinflammatory and vasoactive mediators that cells can release) [20].

Masitinib has a favorable safety profile with no significant toxicity at a daily dose of 7.5 mg/kg. Side effects of masitinib are similar to other tyrosine kinase (TK) inhibitors. Long-term use of masitinib may cause gastrointestinal (nausea, vomiting), hematological (anemia, lymphopenia, neutropenia, thrombocytopenia), dermatological (eyebrow and facial edema, rash) and other disorders (fever, jaundice, dehydration, symptoms, deterioration of body health, hypokalemia and thrombosis). Liver function should be carefully controlled in these patients [13].

7. Alzheimer’s disease (AD)

The goal of therapy in AD is to symptomatically treat cognitive impairment and preserve patient’s function for as long as possible. Other goals include managing psychiatric and behavioral sequelae. Current treatments for AD do not seem to prolong life, cure AD, or halt or reverse the pathophysiologic processes of the disease [21].

7.1 FDA-approved therapies

Many medications can cause psychosis in people with dementia, but some medications are more common. Benzodiazepines and other sedative-hypnotics, anticholinergics, and antipsychotics have been associated with cognitive impairment. Additionally, H2 receptor antagonists, corticosteroids, and opioids such as pethidine have been associated with delirium or altered consciousness. Because medication use is associated with a return of cognitive symptoms, medication review and management are important [22].

The US Food and Drug Administration (FDA) has approved six drugs for treatment: tacrine, donepezil, rivastigmine, galantamine, memantine, and lecanemab. Although aducanumab was quickly approved by the FDA on June 7, 2021, its long-term safety and tolerability require further monitoring and approval. The above FDA-approved treatments are intended to improve symptoms only. Therefore, treatment-modifying strategies are needed to slow, modify, and control the progression of AD [23].

There is interest in developing various drugs that address many aspects of AD pathology, including prevention of Aβ accumulation, tau phosphorylation, oxidative stress, and mitochondrial autophagy dysfunction. Many of these drugs are currently in clinical trials [24].

7.2 Drugs under investigation

7.2.1 β-Secretase inhibitor

Beta-secretase inhibitors often reduce beta-amyloid production. However, clinical trials of β-site APP-cleaving enzyme 1 (BACE1, also known as β-secretase 1) have been unsuccessful. Verubecestat, Lanabecestat, and Atabecestat are some of the acylguanidine class molecules that have entered late clinical trials. However, they failed to reach the market due to toxicity or lack of appropriate treatment [25].

7.2.2 γ-Secretase inhibitors

Semagacestat is a non-selective small molecule γ-secretase inhibitor whose mechanism of action is identical to that of a β-secretase inhibitor and is designed to reduce Aβ amyloid deposition. In a later phase III trial, the trial was stopped due to greater weight loss in patients taking semaacestat compared to the placebo group and side effects such as skin cancer and infection. Similarly, a phase II study of avagacestat in patients with mild-to-moderate AD was discontinued due to AEs such as cerebral microbleeds, diabetes, and cancer [26].

7.2.3 Anti-tau drugs

The role of Tau is not fully understood, but studies have shown that it plays an important role in the assembly and stability of cytoskeletal microtubules. Abnormal hyperphosphorylation of Tau (p-tau) reduces its binding affinity to microtubules, and abnormal phosphorylation of Tau causes aggregation and formation of NFTs. Anti-tau therapy mainly involves three aspects: preventing excessive phosphorylation and accumulation of tau, stabilizing microtubules, and ensuring the removal of tau [23].

7.2.4 GSK-3β inhibitor

GSK-3β inhibitors prevent hyperphosphorylation of tau protein. Studies have shown that GSK-3β can reduce abnormal Tau phosphorylation and amyloid production in vitro and in vivo, making it a promising treatment-modifying therapy for AD. Lithium was first used in psychiatry, discovered by Australian psychiatrist John Cade in 1949 and was widely used in the treatment of manic episodes [27].

In recent years, lithium has been shown to be an inhibitor of GSK3, which is involved in glucose metabolism, cell signaling and proliferation, and control of glial cell function. Lithium prevents amyloid formation and tau hyperphosphorylation. Long-term use of lithium therapy is associated with serious adverse events (SAEs), and it requires constant monitoring of lithium concentration in the blood. There is a medical need for safer and better lithium [23].

7.2.5 Tau aggregation inhibitor

Tau protein accumulation is associated with neuron loss. Tau aggregation inhibitors such as methylene blue chloride (methblue) and hydromethanesulfonate (LMTM) can reduce Tau accumulation. Methylene blue chloride (methylene blue) is also a drug with a long history of use, mainly in the treatment of malaria, hyperferremia and carbon monoxide poisoning, and as a histological stain.

In a 24-week phase II study, methylene blue chloride failed to show clinical benefit in AD [28].

7.2.6 “Multi-target” agents on AD

7.2.6.1 γ-Carbolines

Dimebon is a gamma-carboline derivative compound combined with methylene blue. Dimebon is a multi-purpose drug. Its activities include protecting neurons from death, reducing protein synthesis, and increasing autophagy [23].

However, owing to a lack of statistically significant efficacy, the use of dimebon for AD was not confirmed through a phase II clinical trial [29].

7.2.6.2 Phenothiazine

Phenothiazine-based theranostic compounds inhibit Aβ aggregation in a double transgenic mouse model of AD and can serve as near-infrared fluorescence (NIRF) imaging probes of amyloid plaques in AD [30].

Unfortunately, there are currently no reports of phenothiazine studies for the treatment of AD in the PubMed database.

7.2.6.3 Carbazoles

P7C3 is a neuroprotective aminopropylcarbazole found during postnatal hippocampal neurogenesis studies. P7C3, named P7C3 because it is the third compound (C3) in the seventh pool (P7), protects young hippocampal neurons and prevents neuron death. It has also been shown to inhibit cognitive function in terminally aged mice. Unfortunately, there are no reports of clinical studies of P7C3 in the treatment of AD in the PubMed database [23].

7.2.6.4 5-HT

Idalopirdine is a novel selective 5-HT6 receptor antagonist that binds to ChEI, improving central acetylcholine levels and neuronal activity and improving cognition in animal models. A phase II proof of concept (PoC) study combining successful treatment of AD with idalopirdine plus donepezil showed significant improvement in cognitive functions in AD, such as ADAS-implant and MMSE scores [31].

On the other hand, Phase III development of idalopidine (“OLEX”, idalopidine alone and “MEMOLEX”, idalopidine plus memantine) for the treatment of AD did not demonstrate significant benefit. AVN-101 is a potent 5-HT7 receptor antagonist. AVN-101 shows good oral bioavailability, increases blood-brain barrier permeability and has low toxicity and reasonable efficacy in animal models of central nervous system disease [23].

7.2.6.5 Tyrosine kinase inhibitor

Masitinib is an oral tyrosine kinase inhibitor that exerts neurodegenerative effects in neurodegenerative diseases such as multiple sclerosis by inhibiting mast cell and microglia/macrophage activity [32].

Recently, a phase III clinical trial of masitinib in AD was completed and showed that masitinib improved ADAS-cog and ADCS-ADL scores [33].

8. Huntington’s disease (HD)

8.1 Current therapeutic options for Huntington’s disease

The most commonly used HD medications are designed to reduce chorea. One of the main features of HD is degeneration of the basal ganglia, especially the striatum, which is associated with the development of chorea [34].

Patients with chorea whose daily activities are not affected should be recognized and educated. If chorea requires medical treatment, drug options may be considered. Dopamine receptor blockers such as haloperidol, risperidone, and olanzapine have been used in the past and have additional benefits in treating depression and behavioral disorders. However, the disadvantage of atypical and atypical drugs is that they increase the risk of sudden death and the use of drugs for PD [35].

Since its approval, tetrabenazine has been frequently used to treat chorea, but its use is generally limited due to the risk of side effects. In a clinical trial, deutetrabenazine, approved by the FDA in April 2017, showed a statistically significant improvement in chorea in 90 HD patients compared to placebo [36].

The most common side effect in the deutetrabenazine group was drowsiness. Events such as depression and akathisia were similar between the drug and placebo groups. Amantadine has also been reported to have an effect on chorea. Anticholinergic drugs, such as benztropine, do not help treat chorea because they are actually prodopinergic drugs [34].

Depression is the most common symptom associated with HD, and most experts agree that it can be treated with serotonin reuptake inhibitors. Patients with obsessive-compulsive disorder, anxiety, and depression may also respond to this medication. Valproic acid and carbamazepine can help reduce anxiety and depression [37].

Both typical and atypical antipsychotics may be useful in treating mental illness, mood swings, and anxiety, but doses should be kept to a minimum to minimize the risk of extrapyramidal side effects [38].

Riluzole is a CNS glutamate neurotransmission inhibitor that exhibits neuroprotective effects in clinical models of HD and HD transgenic mice [39].

Ifenprodil, a specific antagonist of NR2B (NMDAR isoform), reduces excitotoxic cell death in medium spiny neurons in HD transgenic and wild-type mice after exposure to NMDA [40].

Minocycline, a second-generation tetracycline that inhibits the caspase pathway, has shown some benefit in mouse models of HD. Meclizine exerts neuroprotective effects and inhibits apoptosis in mouse models [41].

9. Parkinson’s disease (PD)

PD is a neurodegenerative disease caused by the death of a type of neuron that plays a fundamental role in the production of dopamine in the brain. There is no cure for PD, but therapies including drugs, surgery and rehabilitation can reduce symptoms. The medicine that increases the amount of dopamine in the brain, is the most common medication for PD [42].

9.1 Management of motor symptoms

Current treatment is mainly based on restoring dopamine levels, with levodopa considered the main option. However, levodopa administration has limitations due to the occurrence of side effects, of which dyskinesia is a significant problem [43].

Additionally, as the disease progresses, patients become less responsive to dopaminergic medications and require increasingly frequent doses of dopaminergic medications [44].

Therefore, current levodopa formulations contain decarboxylase inhibitors, either carbidopa or benserazide. Decarboxylase inhibitors work by preventing the peripheral metabolism of dopamine and increasing the bioavailability of the drug [45].

However, to avoid problems caused by using too much of one drug, it is recommended to give levodopa simultaneously with other drugs [46].

These medications include rasagiline, safinamide, selegiline, and monoamine oxidase B (MAOB) inhibitors, which have been shown to increase dopamine levels [47].

Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone have also been used. These tools improve dopamine levels and increase physical activity because they promote the absorption of levodopa in the intestine, where most of this enzyme is located [43].

Another class of drugs are dopamine agonists, such as ropinirole and pramipexole, which have been described as safe and effective as monotherapy and in combination with levodopa. In this group, rotigotine is available as a transdermal patch that provides continuous dosing, while apomorphine is available as an injection or subcutaneous infusion to rescue potency change in patients with systemic disease [43].

9.1.1 Invasive treatment options for motor symptoms

Advanced treatments are available for patients with motor disorders or dyskinesias that cause dysfunction and do not improve even with appropriate drug therapy. Deep brain stimulation (DBS), levodopa-carbidopa enteral suspension, and continuous subcutaneous infusion of apomorphine are the best-known alternatives [43].

DBS reduces downtime and improves patients’ quality of life more than any other treatment. National Institute for Health and Care Excellence (NICE) guidance recommends use in the final stages of the disease [48].

Although concurrent dopaminergic therapy is necessary, sometimes the dose can be reduced by 60% after starting treatment [49].

Currently, DBS has proven to be one of the most promising and safe methods of treating PD. Although proven to be safe, surgery is not without risks; the most important being seizures associated with DBS implantation [50].

However, this technology has changed a lot in the last 20 years, the number of side effects has decreased and more targeted treatment of the needed areas has been enabled, supported by clinical pathology. Therefore, DBS appears to be an improved treatment modality for various neuropathologies, including PD [51].

Moreover, Levodopa-Carbidopa Enteral Suspension is another surgical method that can provide safety by placing a permanent tube through percutaneous endoscopic gastrostomy (PEG) connected to a portable external device. This treatment prevents changes in levodopa levels, thus shortening drug withdrawal times and reducing the risk of dyskinesia. However, adverse outcomes and costs led 34% of patients to discontinue the study after 4 years [52].

Finally, continuous subcutaneous infusion of apomorphine allows continuous administration and has the advantage of not requiring surgery. Additionally, this type of treatment does not require the use of high doses of levodopa every day, and some cases in which levodopa administration is not necessary are described. However, a study found that after the first year, half of patients abandoned treatment due to ineffectiveness and poor quality [49].

9.2 Management of nonmotor symptoms

Cognitive impairment, depression, sleep disorders, and functional impairments are non-motor problems in PD. The most common medications used to treat psychosis are acetylcholinesterase inhibitors such as donepezil, galantamine, and rivastigmine [43].

For depression, people with PD are often treated with serotonin/norepinephrine reuptake inhibitors (SNRIs), such as duloxetine, desvenlafaxine, milnacipran, and venlafaxine. Other treatments include benzodiazepines (e.g., alprazolam, clonazepam, diazepam, and lorazepam), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine and sertraline), tricyclic compounds such as amitriptyline (e.g. amitriptyline, imipramine, and other antitriptyline), imipramine and nortriptyline), buspirone, propranolol, quetiapine and trazodone) [53].

For sleep disorders, amitriptyline, clonazepam, doxepin, eszopipine, melatonin, mirtazapine, and trazadone are frequently used in affected patients. But it is important to consider behavioral therapy as a good option to improve sleep hygiene, reduce stress pressure, and improve depression [54].

Patients with orthostatic hypotension can be treated with fludrocortisone, pyridostigmine, and droxidopa. There are four main groups of medications for reducing urinary incontinence: anticholinergics such as darifenacin, oxybutynin, solifenacin, and tolterodine; Beta-3-agonists, mainly mirabegron; Alfuzosin, silodosin, tamsulosin and more importantly, Alpha-1A Blockers; and SNRIs such as duloxetine. In people with PD, on the other hand, salivation usually occurs due to slow swallowing and can be treated with atropine drops, botulinum toxins A and B, glycopyrrolate, or scopolamine patches [55].

Finally, digestive problems such as constipation are often treated primarily with non-pharmacological measures such as dietary changes (such as consuming high-fiber foods and plenty of fluids). However, in cases where this does not work, medications such as lubiprostone and polyethylene glycol can be given. For other conditions such as nausea and vomiting, the most common treatment options are ondansetron and trimethobenzamide [56].

9.3 Treatments under investigation

Recent research into the genetic basis of PD has led to a better understanding of the pathophysiology of the disease, leading to new therapeutic targets and possible treatments. The difficulty in diagnosing PD is an important problem in terms of its treatment. PD is diagnosed when symptoms occur. As mentioned earlier, not everyone with PD may show symptoms, at least in the early stages of the disease [43].

Additionally, PD can cause symptoms similar to dementia. In this sense, the specific dementia caused by PD should not be confused with the development of AD. It has even been said that the combination of Lewy pathology and Alzheimer’s pathology (beta-amyloid plaques and neurofibrillary tangles) is the strongest correlate of PD dementia [57].

The pathophysiological relationship between these two diseases has led to numerous clinical studies examining the combination of the two diseases (PD and AD) [43].

On the other hand, another limitation of PD treatment is the difficulty of drugs reaching dopaminergic neurons in the nigrostriatal region. The blood-brain barrier filters molecules into the brain, allowing molecules that are smaller or have specific pathways to enter [58].

This phenomenon limits the pharmacological options available for the treatment of neurological diseases. Much research now focuses on increasing the permeability of this barrier to allow entry of molecules that cannot enter the central nervous system. In this sense, the use of forced ultrasound to open the blood-brain barrier to deliver the virus to alpha-synuclein and improve the child’s neurotrophin has been shown to reduce PD-related pathology in the trial model, but the results of this study are limited [43].

One of the biggest problems hindering the control of these diseases is the lack of more complete animals that include important factors such as aging and peripheral diseases, which can also reduce the value of preclinical results [59].

As a result, clinical trials testing potential drugs to alter the progression of PD have yielded mixed results. These results can be attributed to many factors, including the diversity of pathophysiology and clinical manifestations of PD, the difficulty of identifying PD in the early stages, and the lack of targets and outcomes to evaluate drug use [60].

Moreover, we can now only evaluate the effects of the disease by observing the symptoms that are the result of neuronal degeneration (motor and non-motor) and the indirect signs of degeneration (e.g., visual function). Similarly, patients in clinical trials often receive dopaminergic drugs with significant symptoms, making it difficult to see the disease-modifying effects of other treatments. These limitations make it difficult for studies to demonstrate disease modification [61].