Introduction

The brain, spinal cord, and their peripheral nerves are the vital organs that regulate the entire functional processing of the human body. Neuroscience highlights the anatomical structures and physiology of such vital organs as well as their widely distributed neuronal network in the periphery. Neurodegeneration is the structural and functional loss of these nerve cells in the nervous system.¹ Multiple diseases can develop from degeneration of neurons, including Alzheimer's disease (AD), Huntington's disease, Parkinsonism, Lewy body dementia, multiple sclerosis (MS), frontotemporal lobe dementia, prion diseases, and amyotrophic lateral sclerosis (ALS).² These primary neurodegenerative diseases (NDs) could cause secondary mental illnesses such as anxiety, depression, schizophrenia, psychosis, epilepsy and bipolar disorder. 

To mitigate this neuropathy and neuroinflammation, various pharmacological interventions have been utilised, thus coining the term “neuropharmacology”.³

Interplay between neuropharmacology and neurodegenerative diseases 

The neuropharmacological approach addresses neuronal loss through multiple drug-based  approaches:^4,5

• Mechanistic targets within cellular and molecular pathways
• Symptomatic intervention, thereby restoring neurotransmitter levels
• Early diagnosis and progression of diseases, and monitoring of pharmacotherapy through biomarkers. Biomarker types include prognostic, risk, pharmacodynamic, predictive, monitoring, and diagnostic biomarkers
• Pharmaceutical investigation of already existing drugs to target the same pattern of neurodegeneration through the repurposing of drugs
• Application of the novel strategy by the implementation of personalised medicines targeting ND

The neurobiological basis of NDs

NDs are caused by a variety of reasons at cellular and subsequent molecular levels, such as:^4,5,6.7

• Accumulation of abnormal proteins, including alpha-synuclein in Parkinson's disease, huntingtin in Huntington's chorea, and beta-amyloid in Alzheimer's disease; together, these are termed proteinopathies
• Increased calcium ion production and release, and overproduction of reactive oxygen species (ROS) by the mitochondria of cells
• Imbalance in the levels of oxidant and antioxidant species leads to denaturation of protein, peroxidation of lipids, and DNA damage
• Astrocytes and microglial dysregulation lead to overproduction of proinflammatory cytokines, including tumour necrosis factor alpha (TNF𝝰) and interleukin-6 (IL-6)
• Misfolding of proteins, accumulation and degradation of toxic aggregates through a dysfunctional ubiquitin-proteasome system (UPS), and abnormal working of chaperone proteins and autophagic processes
• The most probable reason is abnormal levels of neurotransmitters such as dopamine, catecholamines, and serotonin. These neurotransmitters have vital roles in brain functions, including cognitive capacity, memory retrieval, attitudes, mood stabilisation, and normal behaviours

Symptomatic treatment

Symptomatic treatment involves restoring the levels of neurotransmitters in various regions of the brain and spinal cord, thereby managing distressing clinical symptoms, such as cognitive decline, impaired thinking, tremors, unusual stress, mood stability, and sleep patterns.^4,5,6.7

• In Parkinson's disease, treatment aims to maintain the levels of dopamine in the brain; this can include:
  • Precursors of dopamine, such as levodopa
  • Dopamine agonists, such as ropinirole
  • Dopamine metabolism inhibitors, such as monoamine oxidase inhibitors (MAOIs) rasagiline, and catechol-O-methyltransferase inhibitors (COMTIs), tolcapone
• Alzheimer's disease treatment restores the levels of acetylcholine (Ach) through various methods, including:
  • Acetylcholinesterase (AchE) inhibitors (AchEI), such as donepezil, inhibit AchE from degrading Ach, thereby restoring Ach levels
  • Memantine blocks N-methyl-D-aspartate receptor (NMDA)-type glutamate receptors to prevent excessive firing of action potentials, including over-excitation of neuronal cells, consequently maintaining neuronal integrity
• Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, stabilise mood problems
• Lorazepam and triazolam belong to the class of benzodiazepines, which treat dementia-related degeneration issues such as lethargy and lack of sleep
• Reserpine and quetiapine are antipsychotic medications used to mitigate aggressive behaviours

Disease-modifying agents

These drugs alleviate the pathogenesis (development) of the disease, including:^7,8,9

• Lecanemab and solanezumab decrease the accumulation of amyloid-beta (Aβ) plaques.
• Semorinemab binds to the N-terminal of tau proteins, thereby reducing tau aggregation, spread, and hyperphosphorylation.
• Antisense oligonucleotides (ASOs), such as tominersen, deplete levels of mutant huntingtin (mHTT) protein through gene silencing techniques.

Drugs targeting neuroinflammation

Inflammation of neurons is always triggered by the neuroglial cells, such as microglia, which further activate the inflammatory proteins, producing acute and chronic inflammation in the neurons of the brain and spinal cord. Therefore, drugs are used to mitigate these entire inflammatory processes. These drugs include:^7,8,9

• Sargramostim changes the microglial state from a pro-inflammatory M1 state to an anti-inflammatory M2.
• Etanercept is a TNF-α inhibitor clinical trial phase 2 drug that inhibits the inflammatory pathway.
• Leukotriene antagonist montelukast is an anti-inflammatory and is used in Phase II clinical trials for anti-Alzheimer effects.

Neuroprotection and neuron survival-enhancing agents

By reversing oxidative stress, the survival rate of neurons can be enhanced, and neuroprotection is promoted. For example:^10,11

• Melatonin is an anti-inflammatory agent that decreases neuronal injury
• In ALS, riluzole prevents the excitotoxic potential of neurons and, consequently, preserves neuronal function

Novel approaches

Multiple novel strategies have been reported in scientific literature to enhance neuronal survival and prevent neuronal damage, including:^7,8,9,11

• Autophagy activators, such as mTOR (mammalian target of rapamycin), inhibit mTOR kinase activity to eliminate unnecessary misfolded proteinous substances
• Natural compounds can promote normal lysosomal function to remove toxic components of neuronal cells because lysosomes are dysfunctional in neurodegeneration

FAQs

How are microglia involved in neuroinflammation?

Microglia in the central nervous system (CNS) have multiple pattern recognition receptors (PRRs), such as nod-like receptors (NLRs), tumour necrosis factor (TNF), interleukin-1 receptors (IL-1R), and toll-like receptors (TLRs). Upon ligands binding to PRRs (such as amyloid beta (amyloid-β), TLR4, and α-synuclein-TLR2), signal transduction pathways take place, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). They then produced pro-inflammatory chemicals such as interleukin. These inflammatory chemicals inflame the neuronal cells, leading to the structural and functional loss of nerve cells.⁷

How are microglia involved in neuroinflammation?

Microglia are part of the central nervous system's defence system. Microglia survey the whole nervous system to find harmful substances and remove them from healthy cells.⁷

What happens to nerves when microglia are damaged?

When microglia are damaged, their defensive role is compromised because they are unable to detect intracellular toxic dead neurons, which will trigger more oxidative stress and exacerbate neuroinflammation, thus leading to the development of neurodegenerative diseases.⁷

Summary

Neuropharmacology is an intervention for diseases caused by degeneration in the nervous system. Multiple therapeutic drugs have been investigated to target different inflammatory mechanisms for the treatment of neurodegeneration. Primarily, neuropharmacology focuses on reducing oxidative stress and subsequent inflammation. A number of pharmacological drugs have been utilised to increase autophagy and block the enzymatic degradation of neurotransmitters. Therefore, the aim is to normalise levels of neurotransmitters to maintain normal physiology. When depleted levels of the neurotransmitters are not restored, clinical problems, including proteinopathy and neuropathy, could remain, thereby causing neurodegenerative disorders. Alternatively, the pathogenesis of diseases, including proteinopathies, is targeted to achieve normal physiological functioning of the brain and spinal cord.