Antiepileptic and Neuroprotective Biochemical Actions of Sabinene Prevent the Development of Pentylenetetrazol-Induced Seizures and Neuropsychiatric Comorbidities in Mice.

Epilepsy is a long-term neurological disorder that leads to disability with neuropsychiatric comorbidities. Studies have shown that neurochemical imbalances involved in the disease are linked to heightened oxidative and inflammatory pathways, which significantly affect the severity of the disease. As a result, substances that have antioxidant and anti-inflammatory effects might help in managing the condition. Hence, this study investigated the effects of sabinene, a natural monoterpene in essential oils, against pentylenetetrazol-induced seizure kindling and neuropsychiatric comorbidities in mice, revealing insights into the neurochemical, antioxidant, and anti-inflammatory biochemical mechanisms involved. Male Swiss mice in adulthood were pretreated with sabinene (5 and 10 mg/kg) or diazepam (3 mg/kg) 30 min prior to pentylenetetrazol-induced seizures, with injections administered every other day for 28 days. We conducted behavioral assessments using a Racine scale (0-6) and evaluated comorbidities such as cognitive impairments and depression. Neurochemical, antioxidant and anti-inflammatory biochemical mechanisms of the antiepileptic effect of sabinene against pentylenetetrazol-induced kindling were analyzed in the prefrontal cortex and hippocampus, two brain regions largely involved in the disease's onset and development. Sabinene inhibits pentylenetetrazol-induced seizures evidenced by the reduced frequency and severity of seizure episodes. Sabinene decreases motor activity, reverses pentylenetetrazol-associated spatial/non-spatial memory deficits, increases sociability, and lowers the depressive symptoms. These behavioral changes reversed by sabinene were accompanied by reduced prefrontal-hippocampal glutamate release and increase GAD enzyme. Consistent with this, sabinene elevated IL-10 in both brain areas while also increasing the levels of prefrontal pro-inflammatory cytokines, such as TNF-α and IL-1β. However, sabinene reduced TNF-α and IL-1β in the hippocampus, as well as oxidant markers (malondialdehyde, nitrite), and increased antioxidant systems in both brain regions compared to the pentylenetetrazol cohorts. Overall, sabinene's antiepileptic and neuroprotective effects include modulating neurotransmitter imbalances, inhibiting oxidative stress, and modulating cortical neuroimmune dysfunction.