Page 9 - BH-2-2

Brain & Heart Oxidative stress and neurological disorders

activation, mitochondrial dysfunction, and subsequent Affected cellular pathways include activation of glycogen
cellular apoptosis. synthase kinase-3β activation, the Akt pathway, loss of
mitochondrial permeability, alterations in glutamate
2.1. Role of antioxidants metabolism, dysregulation of cytokine, and inflammation

Oxidative stress is a pivotal factor in most chronic involving microglial. 29 Ultimately, these events
neurological disorders, making antioxidants a promising culminate in neuronal loss or irreparable nerve injury.
therapeutic approach by reducing oxidative stress through Understanding these cellular pathways holds promise for
the quenching/scavenging of free radical intermediates. identifying potential novel therapies for acute and chronic
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Antioxidants effectively interrupt the cascade of oxidative neuronal and vascular injuries. Studies have reported that
stress reactions. Within biological systems, inherent deficiency in the PINK1 gene, responsible for maintaining
endogenous antioxidants maintain homeostasis. These mitochondrial calcium homeostasis, leads to impaired
antioxidants include enzymatic entities such as superoxide respiration and increased production of ROS due to
dismutase (SOD), glutathione peroxidase, and catalase, as inhibition of complex 1 in the mitochondrial electron
well as non-enzymatic compounds such as glutathione, transport chain. Antioxidant response enzymes (AREs)
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α-lipoic acid, uric acid, and coenzyme Q10. Another are activated upon binding with the transcription factor
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category comprises exogenous or synthetic antioxidants, nuclear factor erythroid 2-related factor 2 (Nrf2). The
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which are synthesized from modifications of natural ARE-Nrf2 complex serves as a neuroprotectant. However,
antioxidant or their conjugation with other effective oxidative stress can disrupt this binding, leading to the loss
molecules. Synthetic antioxidants exhibit superior of Nrf function (Figure 1).
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capacities for scavenging free radicals, metabolic stability,
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and bioavailability compared to natural ones. Examples 4. Role of sigma receptors in neurological
of synthetic antioxidants include propyl gallate, butylated disorders
hydroxytoluene, and polyphenols such as curcumin, Sigma receptors represent a unique class of intracellular
resveratrol, and anthocyanin. Recent research on receptors, distinct from G-coupled receptors and
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synthetic antioxidants has yielded favorable results against ionotropic receptors, and play a significant role
oxidative stress and multiple targets in neurodegenerative in modulating a collection of cellular processes in
diseases. Treatment with various types of antioxidants neurodegeneration. These receptors consist of two
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such as α-lipoic acid , Vitamin C, α-tocopherol, subtypes: sigma-1 and sigma-2, both present in CNS. Each
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crocin, resveratrol, and epicatechin has demonstrated subtype is distinguished by its unique pharmacological
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significant reductions in brain edema, infarct brain properties and structural composition. In recent years,
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volume, oxidative damage, and apoptosis. In addition, sigma receptors have gained interest for their involvement
antioxidant treatment preserves the integrity of the blood- in altering pathways related to cell survival and functions,
brain barrier, ameliorates ischemic injury, and upregulates offering potential therapeutic targets in neurodegenerative
the expression of brain-derived neurotrophic factor and conditions. Sigma-1 receptors are multifunctional
nerve growth factor mRN. Since neurological disorders transmembrane proteins distributed on the mitochondrial
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are multifactorial disorders and oxidative is a common and endoplasmic reticulum membrane, participating
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pathophysiological process affecting multiple targets, in both cellular and intracellular activities. In the CNS,
effective antioxidant therapy or combination therapy could sigma-1 receptors are found on neurons, oligodendrocytes,
have broad therapeutic applicability in clinical trials.
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However, certain challenges hinder translation to clinical microglial cells, and astrocytes, contributing to various
practice, such as low bioavailability, inadequate dosing, physiological activities such as synaptic plasticity and
limited transportation to CNS, and transient retention. the secretion of neurotransmitters such as glutamic acid,
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Nanoparticle-based drug delivery could address some of serotonin, adrenaline, dopamine, and neurosteroids.
these issues. On the other hand, sigma-2 receptors are still under
investigation. Current knowledge suggests that they are
3. Cellular pathways affected during transmembrane proteins with four domains, with N- and
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oxidative stress in the central nervous C-terminals extending into the cytoplasm, and weigh
approximately 18 – 21 kDa. No endogenous receptors
system for sigma-2 receptors have been identified thus far. These
Researchers have shifted their focus toward the cellular receptors are implicated in cholesterol homeostasis,
or metabolic pathways implicated in oxidative stress. sterol transport, and the regulation of intracellular
Stress induces apoptotic injury characterized by early calcium ion concentrations. However, a comprehensive
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membrane fragility loss and genomic DNA destruction. understanding of their chemical structure, physiological
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Volume 2 Issue 2 (2024) 3 doi: 10.36922/bh.2704