ziconotide and Brain-Concussion

Accumulation of calcium following experimental traumatic brain injury (TBI) has been demonstrated to be a prominent pathophysiological component that can compromise mitochondrial functioning and threaten cell survival. The omega-conopeptide SNX-111, also known as Ziconotide, is a potent antagonist of the voltage-gated N-type calcium channel and has demonstrated significant neuroprotective effects against ischemia-induced neuronal injury. To determine whether this compound would be effective in reducing calcium accumulation associated with TBI, SNX-111 was administered intravenously to rats 1 hour following a moderate (2.2 to 2.75 atm) lateral fluid-percussion injury (or sham) at doses of 1 (n = 30), 3 (n = 31), or 5 (n = 30) mg/kg; another group received 0.9% saline solution (n = 35). Brains were processed for calcium 45 (45Ca) autoradiography at 6, 12, 24, 48, and 96 hours following insult. Optical density measurements of 20 cortical and subcortical regions were analyzed. Injured animals administered saline solution exhibited a significant increase in 45Ca uptake within 12 regions ipsilateral to the site of injury. The most prominent increases were evident throughout the ipsilateral cerebral cortex. SNX-111 reduced the injury-induced calcium accumulation within the ipsilateral cortex in a dose-response fashion when measured at 6, 12, and 48 hours after insult. These drug-induced reductions in calcium accumulation were as high as 75% in the ipsilateral cerebral cortex, and up to 50% in other ipsilateral regions (including thalamus and hippocampus). Consequently, the results suggest that posttraumatic blocking of the voltage-gated N-type calcium channel after injury reduces prolonged, trauma-induced calcium accumulation.

Topics: Animals; Autoradiography; Brain; Brain Concussion; Brain Injuries; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Calcium Radioisotopes; Cerebral Cortex; Functional Laterality; Hippocampus; Male; Neuroprotective Agents; omega-Conotoxins; Peptides; Rats; Rats, Sprague-Dawley; Thalamus

The omega-conopeptide, SNX-111 (NEUREX Corporation) was administered to rats 1 hour following a lateral fluid percussion brain injury to determine if the drug could reduced the extent and duration of trauma-induced calcium accumulation. Administration at doses of 3 or 5 mg/kg (i.v.) markedly reduced the extent of calcium accumulation as determined using 45calcium autoradiography primarily within the cerebral cortex and hippocampus. The reduction of calcium accumulation was particularly event within the parietal cortex beginning as early as 6 hours and lasting out to 48 hours following injury. Although not as effective as in the cerebral cortex, SNX-111 did exhibit a reduction of calcium accumulation within the dorsal hippocampus especially at 24 and 48 hours after the insult. These preliminary results demonstrate that SNX-111 can reduce the injury-induced accumulation of calcium even when administered 1 hour after the insult and offers this compound as a potential therapeutic treatment for traumatic brain injury.

Topics: Animals; Autoradiography; Brain Concussion; Brain Edema; Calcium; Calcium Channel Blockers; Calcium Channels; Cerebral Cortex; Dose-Response Relationship, Drug; Head Injuries, Closed; Hippocampus; Male; omega-Conotoxins; Peptides; Rats; Rats, Sprague-Dawley; Water-Electrolyte Balance