fg-9041 and Brain-Injuries

Following a traumatic brain injury (TBI), 5-50% of patients will develop posttraumatic epilepsy (PTE) with children being particularly susceptible. Currently, PTE cannot be prevented and there is limited understanding of the underlying epileptogenic mechanisms. We hypothesize that early after TBI the brain undergoes distinct cellular and synaptic reorganization that facilitates cortical excitability and promotes the development of epilepsy.. To examine the effect of pediatric TBI on cortical excitability, we performed controlled cortical impact (CCI) on juvenile rats (postnatal day 17). Following CCI, animals were monitored for the presence of epileptiform activity by continuous in vivo electroencephalography (EEG) and/or sacrificed for in vitro whole-cell patch-clamp recordings.. Following a short latent period, all animals subjected to CCI developed spontaneous recurrent epileptiform activity within 14 days. Whole-cell patch-clamp recordings of layer V pyramidal neurons showed no changes in intrinsic excitability or spontaneous excitatory postsynaptic currents (sEPSCs) properties. However, the decay of spontaneous inhibitory postsynaptic currents (sIPSCs) was significantly increased. In addition, CCI induced over a 300% increase in excitatory and inhibitory synaptic bursting. Synaptic bursting was prevented by blockade of Na(+)-dependent action potentials or select antagonism of glutamate or GABA-A receptors, respectively.. Our results demonstrate that CCI in juvenile rats rapidly induces epileptiform activity and enhanced cortical synaptic bursting. Detection of epileptiform activity early after injury suggests it may be an important pathophysiological component and potential indicator of developing PTE.

Topics: Animals; Animals, Newborn; Biophysics; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Electric Stimulation; Electroencephalography; Epilepsy; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; In Vitro Techniques; Neurons; Patch-Clamp Techniques; Quinoxalines; Rats; Rats, Sprague-Dawley; Valine

Both microglia and astrocytes respond immediately to traumatic brain injury (TBI). The present study was undertaken to examine whether or not excitatory amino acid (EAA) antagonists could attenuate such glial responses.. EAA antagonists, including the broad spectrum EAA antagonist, kynurenic acid (KYN), specific N-methyl-D-aspartate (NMDA) receptor blocker, 2-amino-5-phosphonovalerate (AP-5), and AMPA-KA receptor blocker, 6,7-dinitroquinoxaline-2,3-dione (DNQX), as well as the voltage-dependent ion channel blocker, tetrodotoxin (TTX), were administered into the unilateral hippocampus of rats through a dialysis probe for 30 minutes before the induction of unilateral controlled cortical impact injury. The rats were killed 10 minutes after injury and their brains were processed immunohistochemically for OX42 (marker for microglia) and glial fibrillary acidic protein (GFAP; marker for astrocytes).. Ten minutes after injury, microglial activation with increased OX42 immuno-reactivity was evident in the entire hemisphere including the hippocampus ipsilateral to the injury side. Similarly, swollen astrocytes with increased GFAP expression could be detected exclusively on the injury side. When KYN was administered in situ before injury, both the rapid microglial and astroglial responses in the hippocampus were significantly attenuated. However, AP-5, DNQX and TTX, the voltage-dependent ion channel blocker, at doses which can inhibit each channel activation, failed to attenuate these glial reactions.. These findings indicate that massive ionic fluxes and/or concomitantly occurring EAA release may be closely related to the initiation of microglial and astroglial responses following TBI.

Topics: Animals; Astrocytes; Brain Injuries; CD11b Antigen; Disease Models, Animal; Excitatory Amino Acid Antagonists; Glial Fibrillary Acidic Protein; Gliosis; Hippocampus; Ion Channels; Kynurenic Acid; Male; Microglia; Quinoxalines; Rats; Rats, Wistar; Receptors, Glutamate; Sodium Channel Blockers; Time Factors; Treatment Outcome; Up-Regulation; Valine