Abstract
Gamma-aminobutyric acid (GABA) receptors belong to a ligand-gated ion channels family and are markedly expressed at the axon terminals of retinal bipolar cells. Ascorbic acid (AA), a known and vital antioxidant in the brain can modulate GABA receptors. We postulate that AA would antagonize benzodiazepines' effect via GABA receptor(s) interacting pathway. Here, we evaluated the modulatory sedative effect of AA on diazepam (DZP)'s anxiolytic effects in Swiss albino mice. The anxiolytic study was accomplished by using open-field, hole-board, and by swing and light-dark tests taking DZP as a standard anxiolytic drug. To understand the possible modulatory effects of AA, animals were co-administered with AA and DZP and/or its antagonist flumazenil (FLU). Additionally, an in-silico study was undertaken against GABA(A1), GABA(B1), and GABA(Aρ₁) receptors. Data suggest that AA at 25 mg/kg (i.p.) increased (p<0.05) the number of field cross, rearing, number of hole cross, and swing and residence, while decreased grooming and dark residence parameters as compared to the control and DZP groups. In addition, AA and/or FLU combined with DZP (2 mg/kg, i.p.) reversed DZP-mediated sedative effects in mice. Results from in silico study suggest that AA has good interactions with GABA(Aρ₁) and GABA(B1) receptors. In conclusion, DZP is a GABA receptor agonist and AA may reverse DZP-mediated sedative effects in a non-competitive binding fashion in mice through inhibition of GABA(Aρ₁) and GABA(B1) receptors.
Highlights
Ascorbic acid (AA), called vitamin C, is a key micronutrient for normal metabolic function, its action on central nervous system (CNS) has been increasingly reported, given its ability to potentiate gamma-aminobutyric acid (GABA)ergic neurotransmission [1]
AA (25 mg/kg, i.p.) and FLU (2.5 mg/kg, i.p.) significantly (p
Mice treated with FLU evidenced a pronounced increase in NHC, NS, and residence in light (RIL), and reduction in residence in dark (RID) values when compared with AAtreated group
Summary
Ascorbic acid (AA), called vitamin C, is a key micronutrient for normal metabolic function, its action on central nervous system (CNS) has been increasingly reported, given its ability to potentiate gamma-aminobutyric acid (GABA)ergic neurotransmission [1] In this context, Bigelow et al suggested that ascorbate release is mediated by the GABA receptor and located synaptically in rats [2]. GABA(A) receptors existent in the intra-ventral tegmental area exert a pivotal action on narcotic drug-induced AA release modulation in the nucleus accumbens of freely moving rats [3,4] In this context, Naseer and coworkers indicated that AA (0.5 mM) exerts its mediated neuroprotective effect through GABA(B) receptor and protein kinase A-alpha expression modulation in the prenatal rat brain [5]. Research findings by Grigor'ev and Neokesariĭskiĭ (1986) found that at higher doses (10–3 M) AA markedly inhibits, and at lower doses (10–6 M) highly stimulates 3H-GABA binding capacity in rat brain cortical synaptosomes [6]
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