Hemodynamic evolution of acute focal ischemia
Final Report Abstract
Cortical spreading depression (CSD), a slowly propagating wave of neuronal and glial depolarization, is the putative mechanism of migraine aura, and may trigger headache as well. It can be evoked in experimental animals when extracellular K+ concentration exceeds a critical threshold upon chemical or electrical stimulation. Peri-infarct depolarizations (PIDs) are waves akin to spreading depression (SD) originating within ischemic penumbra in experimental animals, as well as in stroke patients. Although SDs in normal brain do not cause injury, PIDs worsen the ischemic tissue outcome by increasing oxygen and glucose utilization and reducing tissue perfusion, thereby exacerbating the metabolic mismatch in compromised tissue . We were interested whether suppression of CSDs and PIDs, the latter shown to be detrimental in stroke, trauma and subarachnoid hemorrhage may afford protection of the brain in order to develop future treatment strategies. Gabapentin, an analgesic and adjunct antiepileptic which also shows efficacy in migraine, inhibits Cav2.1 channels (formerly the P/Q type) by binding the α2δ1 subunit. Pharmacologic inhibition and gain-of function mutations in Cav2.1 channels suppress and enhance CSD, respectively. We could show that Gabapentin, with its very favorable safety and tolerability profile, dosedependently suppressed CSD susceptibility in a migraine model in rats. Unlike other migraine prophylactic agents (i.e. Valproate), chronic treatment was not required for efficacy, nor enhanced it. We could further show that Gabapentin significantly reduced the infarct volume after transient ischemia in mice. However, the frequency and duration of PIDs were not suppressed during the observation period suggesting that gabapentin reduces infarct volume independent of PID suppression. Finally we could successfully provide further support for spreading depression as a relevant target in migraine prophylaxis, and demonstrate the predictive utility of employed spreading depression models for drug efficacy in migraine prophylaxis.
Publications
- Gabapentin acutely suppresses cortical spreading depression. Brain Meeting 2009. Chicago
Hoffmann U, Kudo C, Dilekoz E, Moskowitz MA, Ayata C
- 2010, Neuroscience Seminars, Massachusetts General Hospital, Boston, USA. “Cortical Spreading Depression and Migraine Prophylaxis”
- Cortical spreading depression reconditioning in traumatic brain injury. SAC Meeting 2010. Boston
Hoffmann U, Yung LM, Qin T, Whalen MJ, Waeber C, Ayata C
- Enhanced Subcortical Spreading Depression in Familial Hemiplegic Migraine Type 1 Mutant Mice. Neuroscience Meeting 2010
Eikermann-Haerter K, Yuzawa I, Qin T, Wang Y, Baek K, Kim YR, Hoffmann U, Dilekoz E, Waeber C, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C
- Gabapentin suppresses cortical spreading depression susceptibility. J Cereb Blood Flow Metab 2010; 30: 1588-92
Hoffmann U, Dilekoz E, Kudo C, Ayata C
- Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice. J Cereb Blood Flow Metab 2010
Khuman J, Meehan WP, Zhu X, Qiu J, Hoffmann U, Zhang J, Giovannone E, Lo EH, Whalen MJ
- 2011, Vasospasm Meeting 2011, Cincinnati, Ohio, USA. “Subarachnoid hemorrhage increases the susceptibility to ischemic stroke but not to periinfarct depolarizations after middle cerebral artery occlusion”
- Enhanced Subcortical Spreading Depression in Familial Hemiplegic Migraine Type 1 Mutant Mice. J Neurosci 2011; 31: 5755-63
Eikermann-Haerter K, Yuzawa I, Qin T, Wang Y, Baek K, Kim YR, Hoffmann U, Dilekoz E, Waeber C, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C
- Gabapentin reduces infarct volume but does not suppress peri-infarct depolarizations. Brain Meeting 2011, Barcelona
Hoffmann U, Lee JH, Qin T, Eikermann-Haerter K, Ayata C
- Gabapentin reduces infarct volume but does not suppress peri-infarct depolarizations. J Cereb Blood Flow Metab. 2011, Epub Apr 20
Hoffmann U, Lee JH, Qin T, Eikermann-Haerter K, Ayata C
- Oxcarbazepine does not suppress cortical spreading depression. Cephalalgia 2011; 31: 537-42
Hoffmann U, Dilekoz E, Kudo C, Ayata C
- Subarachnoid hemorrhage increases the susceptibility to ischemic stroke but not to peri-infarct depolarizations after middle cerebral artery occlusion. Vasospam Meeting 2011. Cincinetti, Ohio
Hoffmann U, Lee JH, Park Hopson K, Yzawa I, Qin T, Nozari A, Ayata C
