Targeting calcium dependant/cAMP/PKA/CREB pathway and GABAergic transmission by drotaverine and hesperidin for amelioration of tardive dyskinesia

Antipsychotics, commonly used for anxiety and psychosis, are linked to severe side effects like fatal ventricular arrhythmias, sudden cardiac death, and movement disorders, limiting their therapeutic use. This research aimed to explore novel mechanisms to treat psychotic anxiety while minimizing these risks. Drotaverine activates the cAMP/PKA/CREB pathway, while Hesperidin inhibits dopaminergic hyperactivity. Using a reserpine-induced orofacial dyskinesia model, which mimics tardive dyskinesia linked to oxidative stress, reserpine (1 mg/kg, s.c) was administered for three days. Rats were pre-treated with drotaverine (8 mg/kg, p.o) and hesperidin (50 mg/kg, p.o) for five days. Statistical analysis via one-way ANOVA and Dunnett’s test showed that reserpine significantly increased vacuous chewing movements (VCMs), tongue protrusions (TPs), and reduced locomotion and exploration. Pre-treatment with drotaverine and hesperidin reduced VCMs and TPs. Reserpine-treated rats had lower catalase and higher lipid peroxidation (LPO) levels, indicators of oxidative stress, which were reversed by the drugs. Additionally, drotaverine improved cognition by modulating the cAMP/PKA/CREB pathway, and Hesperidin offered neuroprotection through GABAergic transmission. Both drugs, alone or in combination, demonstrate potential as alternative therapies for psychotic anxiety with neuroprotective benefits.