Gauging the role and impact of drug interactions and repurposing in neurodegenerative disorders

Abstract

Neurodegenerative diseases (ND) are of vast origin which are characterized by gradual progressive loss of neurons in the brain region. 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 world-wide. Multiple factors like aging, genetic mutations, environmental factors, gut microbiota, blood-brain barrier microvascular complication, etc. may increase the predisposition towards ND. Genetic mutation is a major contributor in increasing the susceptibility towards ND, the concept of one disease-one gene is obsolete and now multiple genes are considered to be involved in causing one particular disease.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 be treated 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.

Treatment of apathy in Parkinson's disease: A bayesian network meta-analysis of randomised controlled trials

“…Many of the studied medications are neurotropic agents which require transition across the blood-brain barrier and then interact with various receptors within the central nervous system. Such medications are also prone to drug-drug interactions, which range from altered pharmacokinetics to potentially life-threatening ones such as serotonin syndrome and sedation [ 54 , 55 ]. Furthermore, polypharmacy is highly prevalent in PD as patients tend to have multiple medical comorbidities.…”

Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases

“… Recognizing new targets from meta-analyses and retargeting studies of known or old drugs. Computerized studies are a great asset because deep-learning arrays and other information technology approaches are becoming increasingly more available [ 225 , 226 , 227 , 228 , 229 ]. …”

Hydrogen Ion Dynamics as the Fundamental Link Between Neurodegenerative Diseases and Cancer. Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis in Multiple Sclerosis

“…In MS there is a pro-inflammatory gene, Il-6, responsible for the activation of microglia and astrocytes and transportation of B and T lymphocytes into the brain. In addition, Il-7 gene, which also is a strong proinflammatory factor, plays a key role in the modulation of T lymphocytes [234]. Bacterial metabolites can cross the blood brain barrier (BBB) and activate toll-like receptor 4 which aggravates neuroinflammation and neurodegeneration.…”