Exploring Neuropharmacology's Impact on Managing Neurodegenerative Ailments
The human brain, spinal cord, and their peripheral nerves, collectively known as the nervous system, are vital organs that regulate the entire functional processing of the human body. Unfortunately, these organs are often the target of neurodegenerative diseases, leading to the structural and functional loss of nerve cells. Some common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, among others.
These primary neurodegenerative diseases can cause secondary mental illnesses such as anxiety, depression, schizophrenia, psychosis, epilepsy, and bipolar disorder. To combat these conditions, various drug-based approaches have been developed.
Neurotransmitter Restoration
In Parkinson’s disease (PD), dopamine replacement therapy remains primary, using levodopa and dopamine agonists to restore dopamine levels and improve motor symptoms. Emerging gene therapies aim to deliver trophic factors like GDNF (glial cell line-derived neurotrophic factor) via viral vectors to support dopaminergic neuron function and survival, showing promising clinical trial results for PD.
Disease-Modifying Agents
Approaches targeting underlying disease mechanisms such as protein aggregation, autophagy dysfunction, and metabolic dysregulation are being developed. For Alzheimer’s disease (AD), drugs targeting amyloid-beta and tau protein pathology are in development. Enhancing autophagy to clear pathological proteins through pharmacological modulation of lysosomal pathways (e.g., TRPML1, TPC2) is advancing as a disease-modifying strategy. Metabolic interventions, including mitochondrial-targeted antioxidants, NAD+ precursors, and AMPK activators, aim to improve neuronal energy metabolism and slow cognitive decline.
Drugs Targeting Neuroinflammation
Chronic neuroinflammation contributes to the progression of AD, PD, and other neurodegenerative disorders. Anti-inflammatory agents, including those targeting inflammatory cytokines and senolytic drugs to remove pro-inflammatory senescent cells, offer novel therapeutic potential.
Neuroprotection
Neuroprotective approaches focus on preventing neuronal death by modulating excitotoxicity and oxidative stress. NMDA receptor (NMDAR) antagonists regulate excitotoxicity and maintain synaptic function, representing key therapeutic targets in multiple neurodegenerative diseases. Gene therapy delivering neurotrophic factors like GDNF aims to provide direct neuroprotection in PD, with ongoing clinical trials assessing safety and efficacy.
Neuron Survival-Enhancing Agents
Growth factors (e.g., GDNF), gene therapies, and metabolic enhancers support neuron survival and functional maintenance. Combining metabolic therapies with anti-inflammatory and amyloid-targeting drugs may synergistically enhance neuron survival and cognitive function.
In conclusion, approved drugs mostly focus on symptomatic neurotransmitter replacement (like levodopa in PD or cholinesterase inhibitors in AD), while cutting-edge approaches increasingly combine gene therapies, metabolic modulation, autophagy enhancers, and anti-inflammatory agents to modify disease progression and enhance neuron survival. Clinical trials, particularly in gene therapy and metabolic interventions, are ongoing to validate efficacy and safety. The neuropharmacological approach addresses neuronal loss through multiple drug-based approaches, including mechanistic targets within cellular and molecular pathways, symptomatic intervention, early diagnosis and progression of diseases, monitoring of pharmacotherapy through biomarkers, the repurposing of drugs, and the implementation of personalised medicines.
[1] Kordower JH, et al. Gene therapy for Parkinson's disease: clinical trials and beyond. Neurotherapeutics. 2019;16(1):8-18. [2] McGeer PL, McGeer EG. Neuroprotection in Parkinson's disease: current status and future directions. Neurotherapeutics. 2013;10(4):776-785. [3] De Strooper B, et al. Alzheimer's disease: targets for disease-modifying therapy. Nature. 2016;538(7625):413-421. [4] Leavitt BR, et al. Autophagy in neurodegenerative diseases: autophagy-modulating compounds as disease-modifying therapeutics. Cell Death Dis. 2015;6:e1806.
- To address the mental illnesses that can result from neurodegenerative diseases, various drug-based approaches are being developed, similar to the dopamine replacement therapy used in Parkinson's disease to restore neurotransmitter levels.
- In the quest for disease-modifying agents, scientists are focusing on developing drugs that target underlying disease mechanisms, such as protein aggregation and metabolic dysregulation, mimicking the approach for Alzheimer's disease, where drugs targeting amyloid-beta and tau protein pathology are in development.
- The implementation of personalized medicines in the neuropharmacological approach will likely lead to the use of anti-inflammatory agents, like those targeting inflammatory cytokines and senolytic drugs, to remove pro-inflammatory senescent cells, contributing to the long-term maintenance of health and wellness.
