Changes in c-fos expression induced by trigeminal nerve stimulation in the rat brain

Silvia Deriu;Franca Deriu;Eusebio Tolu;FOLLESA, PAOLO

2011-01-01

---

Abstract

Epilepsy in many patients remains poorly controlled despite the introduction of new antiepileptic drugs. Stimulation of the vagus nerve (VNS) has become an effective method for desynchronizing the highly coherent neural activity typically associated with epileptic seizures. This technique has been used in several animal models of seizures as well as in humans suffering from drug-resistant epilepsy (DRE). Stimulation of another cranial nerve, the trigeminal nerve (TNS), can also cause cortical and thalamic desynchronization, resulting in a activity reduction of pharmacologically induced-seizure in awake rats. Moreover, the an antiepileptic action of TNS has been shown in clinical studies, reporting TNS efficacy in patients DRE. These observations suggest that like VNS also TNS has a potential as a therapy for the treatment of DRE. Although it has been suggested an antiepileptic action for TNS, little is known about the brain structures that could mediate this phenomenon. Fos is a nuclear protein that is expressed under conditions of high neuronal activity. We utilized Fos immunoreactivity techniques on Sprague-Dawley rat brains to identify regions that are activated by the left trigeminal nerve stimulation. Anesthetized rats were implanted in the infraorbital branch of the trigeminal nerve (ION) with a bipolar electrode connected to a pulse generator. Three days later, the pulse generator was activated for a 3h treatment using stimulation parameters (30 sec ON, 5 min OFF; continuous cycle; 30 Hz, pulse width of 500 μs, 3.5 mA). A sham control group underwent the same surgery but the electrode was connected to a dummy pulse generator. We found that TNS induced specific increases in nuclear Fos immunolabeling in discrete brain structures, including the amygdale and cortical regions compared to control animals. We found a 4 fold increase in the number of Fos positive cells in the amygdala of TNS rats that resulted statistically significant (P<0.0001) compared to control rats. Moreover, the number of Fos positive cells in the right amigdala was 7 folds grater than the number in the left amygdala (P<0.0001). Likewise , the number of Fos positive cells in the somatosensory area of the frontoparetial cortex was increased of 2.8 folds (P<0.01) and again a difference between left and right was evident, being the number of Fos positive cells 6.6 folds grater (P<0.001) in the right cortex. These brain structures activated by TNS could be important for genesis or regulation of seizures. The activation of these structures may play a pivotal role in the antiepileptic effect of TNS that could be used as an adjuvant to drugs and/or VNS in those patients that are refractory to treatment.