Gauging The Role And Impact Of Drug Interactions And Repurposing in Neurodegenerative Disorders Part 1
May 14, 2024
ABSTRACT
Neurodegenerative diseases (ND) are of vast origin and are characterized by gradual progressive loss of neurons in the brain region.
The brain is a magical organ that not only controls our thinking, consciousness, and actions but also has amazing memory. The main functions of the brain come from the activity of neurons, which are the basic units of the brain. Each neuron has many synapses and cell bodies, forming a complex network in the brain. These neurons are closely related to memory because our memory is the process of storing, processing, and retrieving information in neural networks.
Neurons are mainly divided into three parts: cell body, dendrites, and axon. Dendrites are the branches of neurons that receive signals from other neurons, and axons are the conductive rods of neurons that transmit information to other neurons. Neurons in brain regions combine into specialized neural circuits that process and store various types of information.
In the brain, the activity of neurons produces electrical signals that can be measured and recorded in what we call an electroencephalogram (EEG). EEG can show how neurons in different areas generate coordinated signals from their responses. These signals are related to various neural activities, including perception, thinking, and memory.
In the brain, different areas have different functions and characteristics. For example, the hippocampus is an important region of the brain associated with long-term memory. In the hippocampus, neurons can form new neural circuits to store and retrieve new information. Other regions, such as the frontal and occipital lobes, are associated with tasks such as working memory and spatial navigation.
Memory is one of the most fascinating functions of the brain. The strength of memory depends on the activity of neurons in areas of the brain. The activity of these neurons can be enhanced largely through exercise. For example, learning new knowledge and skills can promote the formation of new neural circuits in the brain, thereby enhancing memory and cognitive abilities. In addition, exercising, getting enough sleep, and eating a healthy diet can also help improve memory.
In short, there is an inseparable relationship between neurons in brain regions and memory. Neurons are the basic units in the brain, and different neurons form different neural circuits to achieve various complex functions. Therefore, we should cherish our brain and exercise and promote its function through various appropriate methods to improve memory and cognitive abilities. Let's use our brains energetically together! It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in a variety of ways.
Click know 10 ways to improve memory
ND can be classified according to the clinical symptoms present (e.g. Cognitive decline, hyperkinetic, and hypokinetic movements disorder) or by the pathological protein deposited (e.g., Amyloid, tau, Alpha-synuclein, TDP-43).
Alzheimer's disease preceded by Parkinson's is the most prevalent form of ND worldwide. Multiple factors like aging, genetic mutations, environmental factors, gut microbiota, blood-brain barrier microvascular complications, etc. may increase the predisposition towards ND. Genetic mutation is a major contributor to increasing the susceptibility towards ND, the concept of one disease-one gene is obsolete and now multiple genes are considered to be involved in causing one particular disease.
Also, the involvement of multiple pathological mechanisms like oxidative stress, neuroinflammation, mitochondrial dysfunction, etc. contributes to the complexity and makes them difficult to treat by traditional mono-targeted ligands.
In this aspect, the Poly-pharmacological drug approach which targets multiple pathological pathways at the same time provides the best way to treat such complex networked CNS diseases.
In this review, we have provided an overview of ND and their pathological origin, along with a brief description of various genes associated with multiple diseases like Alzheimer's, Parkinson's, Multiple sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Huntington's and a comprehensive detail about the Poly-pharmacology approach (MTDLs and Fixed-dose combinations) along with their merits over the traditional single-targeted drug is provided. This review also provides insights into current repurposing strategies along with its regulatory considerations.
1. Introduction
Neurons are one of the most special types of cells present in the human body. Their physiological role, as well as their cellular structure consisting of axons and dendrites, is very unique as compared to other cells in the human body.
They are present throughout the body but most of them come together to form a complex network of millions of synapses and cell bodies in the brain. The human brain though only small in size and weighing in the range of 1300–1400 g consumes a lot of energy and oxygen as compared to other organ systems (Gallagher et al., 1998; Heymsfield et al., 1985).
Our brain accounts for almost 20% of energy consumption at rest (Gallagher et al., 1998). Most portion of this energy is spent by neurons in maintaining the function at synapses such as neurotransmitter release, recycling of vesicles, reuptake of neurotransmitters, and maintaining, and restoring membrane potentials (Watts et al., 2018).
Moreover, healthy neurons do not store glucose in the form of glycogen and hence are entirely dependent on cerebral blood flow for the requirements of glucose (Rai et al., 2018). Due to such high energy requirements, even a slight mitochondrial dysfunction drastically increases the oxidative stress and makes them susceptible to damage.
Although a few regions in the brain are more susceptible to neuronal degeneration as compared to others, the reason behind this is still not clear. Also, due to a lack of regenerative capacity, the damage is permanent.
Environmental pollution is one of the major risk factors in the development of NDs (Calderon-Garciduenas et al., 2016). Considering the current modern lifestyle and increasing environmental pollution the cases of ND are only going to increase shortly. Currently, Alzheimer's disease (AD) is the most common ND followed by Parkinson's disease (PD).
Even if such diseases have been present for many decades their exact pharmacotherapy is still unavailable.
As a result, in the current scenario, the novel innovations in the field of polypharmacology seem like a ray of hope in combating such multi-mechanistic ND. Apart from polypharmacology, drug repurposing is also an emerging area in the management of various types of ND.
2. Types of ND
Broadly, ND can be classified based on the clinical symptoms observed or the pathological protein present (Kovacs, 2017; Dugger and Dickson, 2017).
2.1. Classification based on clinical symptoms
The focal region/regions at which neuronal damage occurs determines the clinical symptoms associated with the disease.
2.1.1. Cognitive diseases
Diseases that cause significant cognitive decline are classified under this group. Example- AD and Frontotemporal dementia (FTD). The cognitive decline observed in AD is due to lesions/neuronal death in specific neuroanatomical locations such as Hippocampus, Entorhinal complex, and associated cortical regions while in FTD neuronal degeneration is primarily observed in the frontal and temporal lobes.
The advancement in neuroimaging systems and the development of automated segmentation techniques have shed light on the global and subfield details of the Hippocampus. A meta-analysis of MRI studies shows that on average 23–24% bilateral hippocampal volume reduction is observed in AD patients as compared to normal aging controls (Shi et al., 2009; de Flores et al., 2015).
A study conducted in 2015, indicates that a metric system combining hippocampal volume (HV) and hippocampal atrophy rate can give a better understanding of the disease progression from mild cognitive impairment (MCI) to AD (McRae-McKee et al., 2019).
2.1.2. Hypokinetic movement disorder
Such disorders are marked by symptoms such as difficulty in movement, bradykinesia, and rigidity. The most classical example is PD. The loss of dopaminergic neurons in Substantia Nigra creates a deficiency of dopamine in the nigrostriatal pathway which leads to the observed hypokinetic motor symptoms. The clinical symptoms associated with PD can be seen at any time, whenever the neuronal degeneration in Substantia Nigra reaches 30–70% of its total population (Cheng et al., 2010).
2.1.3. Hyperkinetic movement disorder
Hyperkinetic disorders are exemplified by non-volitional movements that occur spontaneously or are superimposed on voluntary movements. Example- Huntington's disease (HD). This is a traditional simplistic way of classification, in the current scenario ND may encompass all three types of clinical features.
2.2. Classification based on pathological protein present
Almost all NDs are characterized by abnormal protein aggregation. These insoluble protein aggregates deposit in various anatomical locations and are considered one of the many reasons leading to neuronal death. Amyloid beta, Tau, TDP-43, alpha-synuclein, and Huntingtin are the major pathological proteins involved.
2.2.1. Amyloid-based classification
Neurodegenerative conditions under this category are primarily characterized by the deposition of the Amyloid-β protein. According to the Amyloid hypothesis theory, Aβ is the major pathological proteinaceous deposition in the senile plaques present in AD (Dugger and Dickson, 2017). Aβ is generated by improper cleavage of a transmembrane protein called the "Amyloid precursor protein" (APP).
APP has diverse physiological functions in the human body some of which include neuronal development, Homeostasis, and intraneuronal transport of lipids like cholesterol (Muller and Zheng, 2012). The processing of APP occurs by 2 pathways (Kojro and Fahrenholz, 2005; Chen et al., 2017). 2.2.1.1. Non-amyloidogenic pathway.
In this pathway, the amyloid precursor protein is cleaved by α-secretase followed by γ-secretase to produce peptide3 (p3) and APPs α. This is a protective pathway since the APPs-alfa released have neuroprotective and neurotrophic activity. This pathway precludes the formation of Amyloid beta.
2.2.1.2. Amyloidogenic pathway. Herein, the APP is initially cleaved by β-secretase followed by γ-secretase which results in the production of Aβ 42 and Aβ 40 fragments. Aβ 40 is freely soluble and hence resists aggregation while the Aβ 42 fragment is highly insoluble and tends to aggregate into oligomers. Such oligomers when accumulated in synapses hamper neurotransmission and subsequently cause neurodegeneration.
The Aβ (1–42) processing of APP protein in AD can be attributed to genetic mutations in APP, PSEN1, PSEN2, and APOE. The details regarding the genetic mutations will be discussed ahead in the review.
2.2.2. Tau based classification
Tau is a microtubule-stabilizing protein present in the axons of neurons. Abnormal tau protein aggregates are indicated in various diseases like AD, frontal-temporal dementia, and PD (Pirscoveanu et al., 2017).
Previously, in AD, tau protein aggregation was considered secondary to the Aβ deposition. However, recent literature related to AD shows that Tau pathology resembles more closely to neuronal degeneration associated with regions like Hippocampus and Entorhinal cortex as compared to Aβ plaques.
In short, it can be concluded that the ancient perspective indicating Aβ as the only pathological protein in AD is no longer valid and both Aβ and Tau are responsible for the complex pathophysiology of AD (Musiek and Holtzman, 2015).
Inside a cell, Tau has important physiological functions such as maintaining the structure of the microtubule and regulating axonal transport. For performing such functions an optimum tau phosphorylation is important.
However, in various ND hyperphosphorylation of tau is observed. In AD deposition of Aβ is thought to exacerbate tau phosphorylation and its downstream pathological processes. Such hyperphosphorylation weakens the microtubule-tau interaction and leads to intraneuronal cytotoxic protein aggregates in the form of Neurofibrillary tangles (NFT).
2.2.3. Alpha-synuclein
α-Synuclein is the major constituent of the Lewy body (Stefanis, 2012). The ND classified under this type shows characteristic deposition of protein aggregate in the form of Lewy bodies. α-synuclein is considered as the primary protein pathology in PD but, its role in the formation of senile plaque in AD is also well documented.
Microscopic analysis of the brain associated with PD and multiple system atrophy (MSA) shows Lewy body inclusions in the neuron and oligodendrocytes respectively (Dickson, 2012). Such Lewy bodies are neurotoxic and contribute to the neurodegeneration associated with PD through multiple mechanisms such as oxidative stress and unfolded protein response (UPR).
Regulation of glucose, modulation of calmodulin, and regulation of vesicle trafficking are a few of the major roles performed by α-synuclein (Emamzadeh, 2016). The genetic mutation (duplication, triplication, and point mutation) in the SNCA gene results in the formation of pathological misfolded α-synuclein and PD.
2.2.4. TDP-43
ALS is the major disease associated with pathological neuronal inclusions of TDP-43 protein. TARDBP is the gene encoding for TDP-43. A missense mutation in the TARDBP gene is thought to be responsible for the pathological cytoplasmic accumulation of TDP-43.
In normal conditions, TDP-43 is localized in the nucleus and binds to ss-DNA, ss-RNA, and proteins and is thought to regulate neuronal plasticity (Prasad et al., 2019). TDP-43 is also thought to have a major pathological role in frontotemporal lobar dementia.
2.2.5. Trinucleotide repeat sequences (Huntingtin/Ataxin)
In such diseases, there is an abnormal expansion of a gene with a trinucleotide. The most common trinucleotide expansion is CAG. Abnormal CAG expansion is observed in HD, Spinal, Bulbar Muscular Atrophy, and Spino-Cerebellar Ataxias.
This repeat causes transcription of aberrantly long proteins having poly-glutamine tracts. Such proteins lose their normal cellular function and instead form cytotoxic protein aggregates which eventually leads to neurodegeneration (Paulson, 2018). An overview of the classification system is shown in Fig. 1.
3. Multifactorial pathological origin
3.1. Ageing
Aging is the major risk factor associated with ND. It is thought that an interplay between aging, genetic predisposition, and environmental factors dictates the type of neurodegeneration that may occur (Wyss-- Coray, 2016). The most common forms of sporadic ND like Parkinson's and Alzheimer's are late onset and usually start to show symptoms at around 65 years of age.
Aging has been thought to contribute to neurodegeneration by various mechanisms such as Genetic instability, Impaired DNA repair mechanism, Low-grade chronic neuroinflammation, Increased Endoplasmic Reticulum stress, microvascular breakdown, decreased antioxidant enzymes, and decreased autophagy.
Genetic instability (GI) refers to the mutations, base mispairing, and strand breaks observed in DNA. Such events are normally repaired by the DNA repair pathways. However, in aged individuals, such damage may become permanent due to impaired DNA repair mechanisms. This leads to a cascade of events resulting in increased oxidative stress, mitochondrial dysfunction, and cell senescence which cumulatively leads to neurodegeneration. (Hou et al., 2019). Autopsy studies of aged brains with no prior neurological complications also show the presence of protein aggregates such as Amyloidβ, Lewy bodies, and TDP-43.
However, such proteins are present in a concentration that is not pathological (Wyss-Coray, 2016; Hou et al., 2019). Such misfolded protein aggregates are cleared by a process called Autophagy. Autophagy can be defined as a process in which misfolded proteins and other cellular debris are subjected to lysosomal degradation via the formation of an autophagosome.
Impairment in micro-autophagy with age may result in the build-up of such misfolded proteins which in turn can promote chronic-low grade neuro-inflammation, and subsequent neurodegeneration (Metaxakis et al., 2018; Walker, 2018). Such impairment in autophagy-related processes can be attributed to hyperactivation of the mTOR pathway and instability of the LAMP2A protein present on the lysosomal membrane. Also, increased aggregated protein burden in the aged brain leads to activation of unfolded protein response (UPR).
In normal homeostatic conditions, UPR tends to increase cell survival by activating the autophagy process, decreasing protein translation, and upregulating chaperones associated with the endoplasmic reticulum. However, sustained activation of UPR in aged individuals may cause activation of pro-apoptotic events leading to cell death and neurodegeneration (Cirone, 2020).
For more information:1950477648nn@gmail.com
