Stroke and Neuroinflammation
The Ford laboratory studies the cellular and molecular mechanisms involved in the pathophysiology of stroke and acute brain injuries. Stroke is the second leading cause of death and invalidity in western society. The Ford laboratory is unique in that we investigate both the vascular and neurological involvement in stroke. Ischemic stroke is accompanied by the increased synthesis of inflammatory molecules, cytokines and reactive oxygen species in neurons, glia and in the cerebral vasculature. The inflammatory response to ischemic brain injury is associated with increased infarct size and poor neurological prognosis; therefore compounds that block inflammation are potentially useful as therapies to treat cerebral ischemia. Work in our laboratory is focused the role of the neuregulin-erbB signaling pathway in regulation of inflammatory responses resulting from ischemic stroke. Neuregulin-1 (NRG-1) is a pleitrophic growth factor structurally related to epidermal growth factor (EGF). We have recently demonstrated that neuregulin-1 is neuroprotective following focal stroke in vivo. The neuroprotection was associated with an inhibition of ischemia-induced inflammatory responses. It was discovered that immediate administration of NRG-1 reduced cell death by 90 percent in the rats that were treated compared with rats that did not receive the compound. It also helped to prevent nerve cell loss after longer intervals, where NRG-1 protected neurons from damage even when administered as long as 13 hours after the stroke's onset. Current studies are aimed at characterizing the specific role(s) for neuregulins in ischemic stroke and neuroprotection in other acute brain injuries, including nerve gas exposure and traumatic brain injury.
Nerve Gas Exposure
Organophosphorus (OP) pesticides and OP nerve agents are irreversible inhibitors of acetylcholinesterase (AChE). Exposure to acutely toxic concentrations of OPs can cause seizures and death and both clinical and experimental animal studies demonstrate neurological deficits in individuals that survive this insult. Current medical countermeasures, which include atropine to antagonize cholinergic effects at muscarinic receptors, an oxime to reactivate AChE and an anticonvulsant to reduce seizure activity, are useful in preventing mortality, but are insufficiently effective in protecting the CNS from seizures and permanent injury. These observations suggest the involvement of mechanisms in addition to accumulation of acetylcholine at central and peripheral cholinergic synapses and evolving evidence implicated inflammatory and apoptotic mechanisms as contributing to acute OP neurotoxicity. Therefore, the goal of the Ford laboratory is to evaluate the therapeutic benefit of NRG-1, a novel neuroprotective compound previously shown to block inflammation and apoptosis following cerebral ischemia, alone or as a complement to the standard therapy for OP poisoning. We have shown that NRG-1 significantly reduced mortality and completely blocked neuronal injury following exposure to the OP nerve agent pesticides. These results suggest that NRG-1 represents a promising therapy following acute OP exposures.
Research Key Words: Stroke, Neuroprotection, Inflammation, Neuregulin, Ischemia, Nerve gas, Trauma