Induction of tolerance against ischemia/reperfusion injury in the rat brain by preconditioning with the endotoxin analog diphosphoryl lipid A

Object. Inflammatory responses and oxygen free radicals have increasingly b een implicated in the development of ischemic brain injury. In some cases, an attenuation of inflammation or free-radical injury can provide tissue pr otection. Diphosphoryl lipid A (DPL) is a detoxified derivative of a lipopo lysaccharide (endotoxin) of Salmonella minnesota strain R595, which is capa ble of stimulating the immune system without eliciting direct toxic effects . In this study the authors examined the influence of preconditioning with DPL on ischemia/reperfusion injury in rats. Methods. Sprague-Dawley rats were injected intravenously with either DPL or vehicle. Twenty-four hours later, some animals were tested for superoxide dismutase (SOD) activity. Others were subjected to a 3-hour period of focal cerebral ischemia and, after a reperfusion period of 21 hours, were killed . Infarction volume, SOD activity, and myeloperoxidase (MPO) activity were assayed in the postischemic animals. Pretreatment with DPL produced significant reductions in cerebral infarctio n and MPO activity in the ischemic penumbra. A significant enhancement of b asal SOD activity was observed 24 hours after DPL treatment (that is, befor e ischemia), and a further enhancement of SOD activity was seen in the isch emic penumbra 24 hours after reperfusion. Conclusions. These data provide the first evidence of a neuroprotective eff ect of preconditioning with DPL in an in vivo model of cerebral ischemia. A lthough the precise mechanisms through which DPL exerts its neuroprotective influence remain to be established, an inhibition of the complex inflammat ory response to ischemia and an enhancement of endogenous antioxidant activ ity are leading candidates.