*3.7. Antidepressant Potential*

RA e ffects at a dose of 0, 3, 10, or 30 mg/kg were investigated in female C57BL/6 mice for 60 min before pilocarpine (300 mg/kg) or pentylenetetrazol (PTZ, 60 mg/kg) injection. Generalized seizure duration and myoclonic generalized tonic-clonic seizure latencies were analyzed by electroencephalographic (EEG) and behavioral methods. The e ffect of an acute RA dose on mice was also evaluated in behavior in the open field, rotarod, novel object recognition, and forced swim tests. In the PTZ model, RA dose-dependently increased generalized seizures and latency to myoclonic jerks and improved pilocarpine-induced myoclonic jerks' latency. Additionally, RA (30 mg/kg) improved the time at the center of the open field, the crossings number and the immobility time in forced swim test [92].

Worldwide mood disorders are the most spreading forms of mental illness and, in main cases, morbidity. According to the World Health Organization (WHO), depression is one of the top causes of morbimortality throughout the world. Depression is a recurrent, potentially life-threatening, and chronic mood disorder that has been estimated to a ffect about 21% of the world population [93]. RA administration (10 mg/kg, daily) in chronic stress Sprague Dawley rats changed depressive behaviors in rats exposed to impulsive stress modal and restored hippocampal brain-derived neurotrophic factor (BDNF) and pERK1/<sup>2</sup> protein expression. Thus, RA could be conceived as a grea<sup>t</sup> molecule in the treatment of depression and in triggering changes in BDNF levels and in ERK11/2 signaling in pharmacological science [94]. In PC 12 cells, RA showed significant neurotrophic e ffects and improved cholinergic functions in correlation with the ERK1/2 signaling pathway and MAPK. RA also caused an extensive up-regulation of pyruvate carboxylase (PC) and tyrosine hydroxylase (TH), involved in serotonergic, GABAergic, and dopaminergic pathways regulation, whereas against corticosterone-induced toxicity it provides neuronal cells protection [95].
