Inhibition of Neurogenic Inflammation as a Novel Treatment for Ischemic Stroke

Abstract

Each year, 15 million people suffer a stroke, of which 5 million die and 5 million are left permanently disabled. Cerebral swelling is of particular concern following stroke as it accounts for much of the death and disability. However, the mechanisms leading to cerebral swelling are not yet fully understood. Recent studies from our laboratory suggest that neuropeptides, and specifically substance P, may be involved in the injury processes that occur following acute insults to the brain such as stroke and trauma, and may be responsible, in part, for edema formation. Levels of substance P are increased following CNS injury, indicative of neurogenic inflammation, and this is associated with injury to the blood-brain barrier, the development of cerebral edema, cell death and functional deficits. Subsequent studies inhibiting neuropeptide release have consistently shown decreased cerebral edema and improved neurological outcome, while substance P antagonists administered after the insult are efficacious in reducing post-stroke cerebral edema and neurological deficits. The current review summarizes the evidence supporting the benefits of inhibiting neurogenic inflammation to treat ischemic stroke.

Neurological disorders and therapeutics targeted to surmount the blood–brain barrier

“…Areas less severely affected are considered to be the penumbra, and comprise cells that are capable of being revived upon timely therapeutic intervention. 60 The ischemic cascade sets off a series of events that culminate in neuronal death. In general, neuron survival and transmission of impulses requires a continuous supply of oxygen and glucose, but in the event of ischemic attacks, there is energy depletion that triggers apoptosis, followed by neuronal death.…”

The Role of the Neuropeptide Substance P in the Pathogenesis of Parkinson’s Disease

“…This detrimental effect of SP was credited to its ability to induce BBB breakdown www.intechopen.com and the subsequent genesis of cerebral oedema (R. Turner and Vink, 2007). Although cerebral oedema does not occur in PD, a decrease in BBB integrity has recently been linked to dopaminergic cell loss and the progression of PD (Bartels, et al, 2008, Kortekaas, et al, 2005.…”

“…CGRP, the most potent vasodilator, increases blood flow, bringing cytokines and inflammatory mediators to the area (Woie, et al, 1993), whereas SP binding to NK 1 receptors increases vessel permeability, leading to plasma extravasation and BBB breakdown (Hokfelt, et al, 2001). Neurogenic inflammation has been well described in the periphery but has also recently been reported to occur in the CNS (Nimmo, et al, 2004, R. Turner andVink, 2007). Another mechanism whereby SP may affect BBB permeability is through histamine.…”

Substance P Antagonists as a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury

“…[61][62][63] In a rodent focal ischemia model, the NK 1 receptor antagonist SR140333 also significantly reduced infarct volume, implying that SP might play a role in exacerbating ischemic damage. 64 Turner and Vink 65 subsequently demonstrated in a rat transient middle cerebral artery occlusion model that NK 1 receptor antagonists given at 4 h after induction of ischemia can reduce BBB permeability and brain edema. There was also an associated improvement in functional deficits as measured using a battery of neurological outcome tests, although no reduction in lesion volume was reported.…”