Escitalopram and Clonazepam Affect Gasotransmitter-related Enzyme (nNOS, HO-2, CBS) Gene Expression in the Rat Brain

Abstract Gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide, play vital roles in neuroplasticity, neurogenesis, and neuromodulation, as well as in regulating oxidative stress, neuroinflammation, and neurotoxicity, all of which are implicated in depressive disorders. This study aimed to investigate whether escitalopram, a selective serotonin reuptake inhibitor, and clonazepam, an anxiolytic Gamma-aminobutyric acid type A receptor agonist, influence the gene expression of enzymes involved in gasotransmitter synthesis in the rat brain. Male Sprague–Dawley rats received chronic escitalopram and clonazepam treatment. Immunohistochemistry and quantitative polymerase chain reaction were performed to assess the expression of genes encoding neuronal nitric oxide synthase, heme oxygenase-2, and cystathionine-β-synthase, enzymes responsible for synthesizing nitric oxide, carbon monoxide, and hydrogen sulfide, respectively, among different brain areas. Chronic escitalopram and clonazepam produced distinct, region-specific changes in neuronal nitric oxide synthase, heme oxygenase-2, and cystathionine-β-synthase expression. Both drugs increased neuronal nitric oxide synthase in cortical and brainstem regions but reduced it in the amygdala and cerebellum; escitalopram additionally enhanced heme oxygenase-2 and cystathionine-β-synthase across multiple sites, whereas clonazepam induced more selective upregulation in the cortex, hippocampus, and hypothalamus with downregulation in the thalamus and striatum. Findings suggest that both escitalopram and clonazepam modulate nitrergic, carbon monoxide and hydrogen sulfide signalling pathways in the rat brain, potentially contributing to their therapeutic and neuroprotective effects in depression and anxiety. The results support the hypothesis that these antidepressant and anxiolytic drugs may exert part of its pharmacological action through modulating gasotransmitter-related mechanisms, offering new insights into its molecular mechanism and providing alternative targets for the development of novel neuropsychiatric medication.