Possible contribution of cerebellar disinhibition in epilepsy.

OBJECTIVE: We hypothesize that loss of inhibition from the cerebellum can lead to cortical activation and seizures. BACKGROUND: The traditional model for development of seizures purports that the source of seizures is increased electrical activity originating from cerebral cortical neurons. Studies have shown a decrease in inhibition results in a shift of cortical activity to a hyperexcitable state, which may lead to seizures. Interestingly, a 1978 study suggested the term "disorder of disinhibition" as a way to describe epilepsy from studies of chronic cerebellar stimulation. DESIGN/METHODS: Cases and experimental studies in which cerebellar lesions have been implicated in the development of seizures were reviewed. Cases in which cerebellar inhibition has been targeted in the treatment of seizures were also included. Twenty-six studies and case reports are presented for this report. RESULTS: The cases show cerebellar lesions can lead to cortical epileptiform activity. Purkinje cell loss is linked to the occurrence of seizures in animals. The majority of patients with cerebellar lesions were seizure free after complete resection, while less than half of patients were seizure free after partial resection. Novel treatments using deep-brain stimulation targeting cerebellar structures demonstrated therapeutic benefits for seizures. CONCLUSIONS: Although pathophysiology is not well-understood, the cerebellum likely plays an inherent role in inhibiting aberrant cortical epileptogenesis. Cerebellar lesions may cause seizures due to loss of the inhibition of cortical areas or through intrinsic epileptic activity. Treatments enhancing cerebellar stimulation have shown therapeutic benefits in treating seizures, which could potentially provide another avenue for treatment.

Transforming growth factor-beta 1 signaling regulates neuroinflammation and apoptosis in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a low-level injury, which often remains undiagnosed, and in most cases it leads to death and disability as it advances as secondary injury. Therefore, it is important to study the underlying signaling mechanisms of mTBI-associated neurological ailments. While transforming growth factor-beta1 (TGF-ß1) has a significant role in inflammation and apoptosis in myriads of other pathophysiological conditions, the precise function of increased TGF-ß1 after mTBI is unknown. In this study, our objective is to study the physiological relevance and associated mechanisms of TGF-ß1-mediated inflammation and apoptosis in mTBI. Using an in vitro stretch-injury model in rat neuronal cultures and the in vivo fluid percussion injury (FPI) model in rats, we explored the significance of TGF-ß1 activation in mTBI. Our study demonstrated that the activation of TGF-ß1 in mTBI correlated with the induction of free radical generating enzyme NADPH oxidase 1 (NOX1). Further, using TGF-ß type I receptor (TGF-ßRI) inhibitor SB431542 and transfection of TGF-ß1 siRNA and TGF-ß antagonist Smad7, we established the neuroinflammatory and apoptotic role of TGF-ß1 in mTBI. Inhibition of TGF-ßRI or TGF-ß1 diminished TGF-ß1-induced inflammation and apoptosis. Further, the enhanced TGF-ß1 activation increased the phosphorylation of R-Smads including Smad2 and Smad3 proteins. By immunofluorescence, western blotting, ELISA and TUNEL experiments, we demonstrated the up-regulation of pro-inflammatory cytokines IL-1ß and TNF-α and apoptotic cell death in neurons. In conclusion, this study could establish the significance of TGF-ß1 in transforming the pathophysiology of mTBI into secondary injury.