Authors:

Dia Dipen Jhaveri

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About Paper:

Organophosphates like chlorpyrifos (CPF) are known for their neurotoxic effects, primarily through acetylcholinesterase inhibition, leading to acetylcholine accumulation and overstimulation of cholinergic pathways. SH-SY5Y cells, a human neuroblastoma cell line, are commonly used to study cholinergic system toxicity. This study investigates the involvement of muscarinic receptors, particularly the M5 subtype, in CPF- induced toxicity in dopaminergic neurons, which also express these receptors. The SH-SY5Y cells will be differentiated into dopaminergic neurons and that model will be utilized for the study. We hypothesize that the M5 muscarinic receptor subtype mediates CPF-induced dopaminergic neuron toxicity. Despite previous studies on muscarinic receptors in cholinergic toxicity, the specific role of M5 receptors in dopaminergic neurons remains unexplored. Addressing this gap, we will assess CPF toxicity, evaluate muscarinic receptor expression, and use M5 receptor antagonists and genetic knockdown in SH-SY5Y cells and primary dopaminergic neurons. We will discover the mechanism of degeneration in dopaminergic neurons using different assays such as cell viability, cell death and immunoblot assays, lipid peroxidation and reactive oxygen species measurements. We will also discover whether neurotoxicity is associated with mitochondrial dysfunctions using several mitochondria-specific assays. Antagonism of M5 receptors is expected to mitigate CPF-induced toxicity, underscoring the receptor's involvement in dopaminergic neuron damage. These findings could lead to new therapeutic strategies against organophosphate-induced neurotoxicity. Keywords: Dopaminergic Neuron; Chlorpyrifos; Organophosphates; Dopamine; SH-SY5Y cells

Source:

Purdue University / 2024

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Co-authors:

Dia Dipen Jhaveri