Biochemistry & Pharmacology: Open Access
Open Access

Enzyme Inhibition Strategies in the Management of Neurodegenerative Diseases: A Biochemical Perspective

Mariana Beatriz Santos^{* *}Correspondence: Mariana Beatriz Santos, Department of Biochemistry and Neuroscience, Federal University of Sao Paulo, Sao Paulo, Brazil, Email:

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About the Study

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a growing global health burden. These conditions are characterized by progressive neuronal loss, synaptic dysfunction, and eventual cognitive or motor decline. A critical biochemical hallmark of many neurodegenerative diseases is the dysregulation of enzymatic activity, often resulting in oxidative stress, protein misfolding, excitotoxicity, and impaired neurotransmitter metabolism. As such, targeting key enzymes through selective inhibition has emerged as a promising therapeutic strategy for slowing disease progression and alleviating symptoms.

One of the most well-studied examples of enzyme inhibition in neurodegenerative therapy is the use of acetylcholinesterase inhibitors in Alzheimer’s disease. AChE is responsible for hydrolyzing acetylcholine in the synaptic cleft, and its overactivity contributes to cholinergic deficits observed in AD. Drugs like donepezil, rivastigmine, and galantamine inhibit AChE, thereby increasing acetylcholine levels and enhancing cholinergic neurotransmission. Although these agents do not cure AD, they offer symptomatic relief and have been widely approved for clinical use. The biochemical specificity of these inhibitors is vital, as off-target effects can lead to undesirable gastrointestinal and cardiovascular side effects.

Another crucial enzyme target in neurodegeneration is monoamine oxidase, which exists in two isoforms: MAO-A and MAO-B. These enzymes catalyze the oxidative deamination of monoamine neurotransmitters such as dopamine, serotonin, and norepinephrine. In Parkinson’s disease, MAO-B inhibitors like selegiline and rasagiline are employed to prolong dopamine activity in the brain by preventing its degradation. This approach helps in reducing motor symptoms and delaying the need for levodopa therapy. Importantly, MAO inhibition also reduces the production of hydrogen peroxide, a byproduct of dopamine metabolism that contributes to oxidative neuronal damage.

Glutamate excitotoxicity, primarily mediated by the overactivation of NMDA receptors, is another pathogenic mechanism in several neurodegenerative disorders. Enzymes involved in glutamate metabolism, such as glutaminase and glutamate dehydrogenase, have been explored as targets for inhibition to reduce extracellular glutamate accumulation. Though still in experimental phases, inhibitors of these enzymes may offer neuroprotective benefits by modulating glutamatergic transmission and preventing neuronal death.

In Huntington’s disease, caspases, which are proteolytic enzymes central to the apoptotic process, play a significant role in neuronal demise. Inhibiting caspase-3 and caspase-6 has been shown in preclinical models to delay neurodegeneration and improve motor function. Similarly, in ALS, matrix metalloproteinases, which degrade extracellular matrix components and modulate inflammatory processes, are upregulated. Inhibitors targeting MMPs have demonstrated potential in preserving the integrity of the blood-brain barrier and reducing neuroinflammation.

Emerging strategies also involve targeting kinases such as glycogen synthase kinase-3β, cyclin-dependent kinase 5, and leucine-rich repeat kinase, which are implicated in tau hyperphosphorylation, synaptic dysfunction, and neuronal death. GSK-3β inhibitors, in particular, are being investigated for their ability to prevent tau aggregation and stabilize microtubules in Alzheimer’s disease. The development of selective inhibitors for these kinases requires a nuanced understanding of their regulatory mechanisms to avoid systemic toxicity, as these enzymes are also essential for various physiological processes.

In addition to small-molecule inhibitors, natural compounds such as flavonoids, alkaloids, and terpenoids derived from medicinal plants have gained attention for their enzyme-inhibitory properties. For instance, curcumin from turmeric has been shown to inhibit AChE and β-secretase an enzyme involved in the formation of amyloid-beta plaques in AD. Similarly, resveratrol, a polyphenol found in grapes, exhibits MAO and MMP inhibitory activity alongside antioxidant effects. These compounds offer multi-targeted approaches with potentially lower side-effect profiles, although their bioavailability and pharmacokinetics require further optimization.

Despite significant advances, several challenges remain in enzyme inhibition therapy for neurodegenerative diseases. Selectivity and blood-brain barrier permeability are key considerations in drug design. Moreover, as neurodegeneration involves multiple overlapping pathways, mono-target strategies may be insufficient. Combination therapies that inhibit multiple enzymes or that couple enzyme inhibitors with anti-inflammatory or antioxidant agents may offer improved outcomes. Furthermore, early diagnosis and intervention are crucial, as many enzyme inhibitors are more effective at halting disease progression than reversing existing damage.

In conclusion, enzyme inhibition offers a compelling biochemical approach to managing neurodegenerative diseases by modulating key pathological pathways involved in neuronal damage. From cholinesterase and monoamine oxidase inhibitors to emerging targets like kinases and caspases, these strategies have shown varying degrees of clinical and experimental success. Ongoing research must focus on enhancing the specificity, safety, and delivery of these inhibitors, while exploring combination and multi-targeted therapies. Ultimately, integrating enzyme inhibition with a broader understanding of disease pathology holds promise for more effective and personalized interventions in the fight against neurodegeneration.