Trigeminal nerve stimulation induces Fos immunoreactivity in selected brain regions, increases hippocampal cell proliferation and reduces seizure severity in rats

Sites and mechanisms by which trigeminal nerve stimulation (TNS) exerts beneficial effects on symptoms of drug-resistant epilepsy and depression are still unknown. Effects of short-term TNS on brain regions involved in the physiopathology of these disorders were investigated in this study. Forty male rats were assigned to three groups: TNS (undergoing electrical stimulation of the left infraorbitary nerve via surgically implanted cuff electrodes); Sham (undergoing surgical procedure but without a stimulation); Naïve rats. The effects of TNS (3-hour session; 30-s ON, 5-min OFF; 30Hz; 500μs; 2mA) were evaluated on: (i) behavioral pattern of pentylenetetrazole (PTZ)-induced seizures as measured by the Racine scale; (ii) c-Fos-like immunoreactivity in discrete brain areas; (iii) hippocampal cell proliferation by bromodeoxyuridine (BrdU)-like immunoreactivity. In comparison with Sham groups, TNS significantly decreased the duration of PTZ-induced seizures (p<0.05) and promoted a faster recovery (p<0.001) by reducing the most severe seizure types. In the TNS group the number of c-Fos-labeled cells was significantly increased (p<0.001) in the trigeminal nuclear complex, nucleus of the solitary tract, locus coeruleus, dorsal raphe nucleus, hippocampus, amygdala, endopiriform nucleus, entorhinal cortex and sensorimotor cortex. In the TNS group the number of BrdU-positive cells in the dentate gyrus was significantly greater with respect to both Naïve and Sham groups. Data show that acute TNS effectively counteracted PTZ-induced seizures and boosted hippocampal cell proliferation in rats. TNS increased c-Fos-like immunoreactivity in brainstem and forebrain structures which play a pivotal role in the physiopathology of epilepsy and depression.