Page 8 - BH-2-2

Brain & Heart Oxidative stress and neurological disorders

to the irreversible changes in neurons that they induce. It is well understood that oxidative stress initiates a
4
For the normal functioning of eukaryotic cells, oxygen series of cellular events that collectively contribute to
is crucial. The demand for oxygen varies depending on neuronal demise. Consequently, targeting oxidative
11
the type of cells and tissues. For example, in the brain, stress represents a potential strategy for interrupting
astrocytes and neurons primarily require a high supply of this detrimental cascade. Therefore, many researchers
oxygen and glucose. are now emphasizing therapeutic interventions aimed
at modulating key components involved in regulating
Despite of essentiality of oxygen, hyperoxia can lead to
toxicity, including neurotoxicity. Although the complete oxidative stress.
pathways affected and the mechanisms underlying this 2. Effects of oxidative stress on the central
situation are not completely understood, many mechanisms nervous system
are directly or indirectly affected by oxidative stress,
ultimately resulting in neuronal death. These mechanisms Due to the high metabolic rate in the central nervous
include mitochondrial dysfunction, altered proteosis, and system (CNS), adenosine triphosphate production is
deregulation of antioxidant pathways. Several studies on notably elevated through the electron transport chain and
animal models and postmortem human brain specimens oxidative phosphorylation. Consequently, neurons and
have reported that increased levels of ROS and reactive glial cells generate substantial amounts of ROS and RNS.
nitrogen species (RNS) lead to damage of proteins, lipids, Neurons and other CNS cells are particularly susceptible to
and nucleic acids. 5 oxidative stress due to their unique biochemical pathways
10
Oxidative stress serves as a common denominator in and intrinsic properties. The influence of oxidative
neuronal loss, responsible for all types of neurological stress on tissue and cellular levels varies depending on
disorders. The role of oxidative stress is evident in the internal structure of impacted brain regions, notably
the hippocampus, prefrontal cortex, amygdala, and
the oxidative damage of many proteins reported in cerebral cortex, which are among the most vulnerable
postmortem studies of Alzheimer’s disease and Parkinson’s regions to oxidative stress. According to the free radical
5
disease. When low concentrations of ROS are maintained, theory of aging proposed by Harman, the CNS is highly
12
they serve as signaling molecules and play a positive role susceptible to oxidative stress due to its substantial oxygen
in defense mechanisms. Astrocytes and glial cells are requirement, which accounts for 20% of the total body
6
responsible for maintaining homeostasis in the brain oxygen utilized for metabolic activities. Neurons exhibit
4
under normal physiological conditions. However, in high heightened sensitivity to oxidative stress due to their
levels of oxidative stress, the appropriate functioning of non-dividing, terminally differentiated nature, rendering
these glial cells is disturbed, leading to a weakened blood- them unable to be replaced even in the face of damage
brain barrier. 7
or mitochondrial dysfunction during their late lifespan.
13
In neurodegeneration, Alzheimer’s disease and Aging of the brain further exacerbates its vulnerability to
Parkinson’s disease account for a significant portion of oxidative stress, leading to increased levels of oxidative
cases, with oxidative stress playing an important role biomarkers such as DNA damage, metal toxicity, and
in both conditions. This oxidative stress can lead to deficits in protein metabolism. In addition, brain aging
the oxidation of mitochondrial DNA, a phenomenon promotes the upregulation of genes that compensate for
closely associated with aging. Studies indicate that age- age-associated deficits, including those involved in protein
related declines in mitochondrial function contribute to folding (e.g., heat shock protein 70 and alpha-crystallin)
impairments in the expression and processing of amyloid and metal-ion homeostasis. Neuronal membranes
precursor protein (APP). The expression of APP is primarily consist of polyunsaturated fatty acids such
8
responsible for the production of ROS in the brain, which as docosahexaenoic acid (DHA), rendering them more
leads to neurotoxicity and the accumulation of amyloid β, susceptible to lipid peroxidation. Neurotransmitters,
14
a hallmark of Alzheimer’s disease. Furthermore, oxidative the chemical messengers facilitating signal transmission
9
stress and mitochondrial dysfunction are implicated in a between neurons and target cells, including dopamine
cascade of events culminating in the loss of dopaminergic and epinephrine, are prone to auto-oxidizable. Excessive
neurons, a defining feature of Parkinson’s disease. The oxygen species react with dopamine, serotonin, and
primary pathology in Parkinson’s disease is the degeneration norepinephrine, initiating their oxidation and leading to
of dopaminergic neurons in the substantia nigra, a region the synthesis of more ROS and quinones in various brain
crucial for regulating motor function. Elevated levels of regions. Ultimately, oxidative stress sets off a cascade
15
oxidative biomarkers, such as 8-hydroxy-guanosine, have of metabolic phenomena culminating in neurotoxicity.
been observed in the brains of Parkinson’s disease patients. 10 ROS toxicity contributes to protein mis-folding, glial cell

Volume 2 Issue 2 (2024) 2 doi: 10.36922/bh.2704