Neuroprotection by Therapeutic Hypothermia

A growing number of recent investigations have established a critical role for leukocytes in propagating tissue damage after ischemia and reperfusion in stroke. Experimental data obtained from animal models of middle cerebral artery occlusion implicate inflammatory cell adhesion molecules, chemokines, and cytokines in the pathogenesis of this ischemic damage. Data from recent animal and human studies were reviewed to demonstrate that inflammatory events occurring at the blood-endothelium interface of the cerebral capillaries underlie the resultant ischemic tissue damage. After arterial occlusion, the up-regulated expression of cytokines including IL-1, and IL-6 act upon the vascular endothelium to increase the expression of intercellular adhesion molecule-1, P-selectin, and E-selectin, which promote leukocyte adherence and accumulation. Integrins then serve to structurally modify the basal lamina and extracellular matrix. These inflammatory signals then promote leukocyte transmigration across the endothelium and mediate inflammatory cascades leading to further cerebral infarction. Inflammatory interactions that occur at the blood-endothelium interface, involving cytokines, adhesion molecules, chemokines and leukocytes, are critical to the pathogenesis of tissue damage in cerebral infarction. Exploring these pathophysiological mechanisms underlying ischemic tissue damage may direct rational drug design in the therapeutic treatment of stroke.

Induction of hypothermia in patients with brain injury was shown to improve outcomes in small clinical studies, but the results were not definitive. To study this issue, we conducted a multicenter trial comparing the effects of hypothermia with those of normothermia in patients with acute brain injury. The study subjects were 392 patients 16 to 65 years of age with coma after sustaining closed head injuries who were randomly assigned to be treated with hypothermia (body temperature, 33 degrees C), which was initiated within 6 hours after injury and maintained for 48 hours by means of surface cooling, or normothermia. All patients otherwise received standard treatment. The primary outcome measure was functional status six months after the injury. The mean age of the patients and the type and severity of injury in the two treatment groups were similar. The mean (+/-SD) time from injury to randomization was 4.3+/-1.1 hours in the hypothermia group and 4.1+/-1.2 hours in the normothermia group, and the mean time from injury to the achievement of the target temperature of 33 degrees C in the hypothermia group was 8.4+/-3.0 hours. The outcome was poor (defined as severe disability, a vegetative state, or death) in 57 percent of the patients in both groups. Mortality was 28 percent in the hypothermia group and 27 percent in the normothermia group (P=0.79). The patients in the hypothermia group had more hospital days with complications than the patients in the normothermia group. Fewer patients in the hypothermia group had high intracranial pressure than in the normothermia group. Treatment with hypothermia, with the body temperature reaching 33 degrees C within eight hours after injury, is not effective in improving outcomes in patients with severe brain injury.

Following an initial impact after spinal cord injury (SCI), there is a cascade of downstream events termed 'secondary injury', which culminate in progressive degenerative events in the spinal cord. These secondary injury mechanisms include, but are not limited to, ischemia, inflammation, free radical-induced cell death, glutamate excitotoxicity, cytoskeletal degradation and induction of extrinsic and intrinsic apoptotic pathways. There is emerging evidence that glutamate excitotoxicity plays a key role not only in neuronal cell death but also in delayed posttraumatic spinal cord white matter degeneration. Importantly however, the differences in cellular composition and expression of specific types of glutamate receptors in grey versus white matter require a compartmentalized approach to understand the mechanisms of secondary injury after SCI. This review examines mechanisms of secondary white matter injury with particular emphasis on glutamate excitotoxicity and the potential link of this mechanism to apoptosis. Recent studies have provided new insights into the mechanisms of glutamate release and its potential targets, as well as the downstream pathways associated with glutamate receptor activation in specific types of cells. Evidence from molecular and functional expression of glutamatergic AMPA receptors in white matter glia (and possibly axons), the protective effects of AMPA/kainate antagonists in posttraumatic white matter axonal function, and the vulnerability of oligodendrocytes to excitotoxic cell death suggest that glutamate excitotoxicity is associated with oligodendrocyte apoptosis. The latter mechanism appears key to glutamatergic white matter degeneration after SCI and may represent an attractive therapeutic target.