A Substance P Antagonist Reduces Axonal Injury and Improves Neurologic Outcome When Administered Up to 12 Hours after Traumatic Brain Injury

Abstract

Previous studies have demonstrated that the compound N-acetyl-L-tryptophan (NAT) reduces brain edema and improves functional outcome following traumatic brain injury (TBI). In this study we examined whether this effect was mediated via the neurokinin-1 receptor, and whether there was an effect on axonal injury. We also explored whether the compound was effective, even when administered at delayed time points. Male Sprague-Dawley rats were subject to acceleration-induced, diffuse TBI and administered NAT, its inactive D-enantiomer, or saline vehicle. In contrast to NAT (2.5 mg/kg), the inactive D-enantiomer was ineffective at improving rotarod motor performance after TBI. NAT also improved cognitive outcome as assessed by the Morris water maze and novel object recognition tests, and reduced axonal injury at 5 and 24 h after TBI as assessed by amyloid precursor protein immunohistochemistry. However, efficacy of the membrane-impermeable NAT was limited to administration within 5 h, whereas administration of a form of NAT, L-732,138 (47 mg/kg), in which a trifluoromethyl benzyl ester group has been added, making it highly lipid soluble and able to cross the intact blood-brain barrier, significantly improved motor outcome, even when administration was delayed by as much as 12 h. We conclude that the neuroprotective effects of NAT are receptor-mediated, and that administration of the membrane-permeable form of the compound can be effective even up to 12 h after TBI.

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

“…NOR has been widely used to measure cognitive function after experimental TBI in rodents. [46][47][48] In the present study, mildly-injured mice spent a similar length of time with the novel object as sham-injured mice, whereas moderately-and severely-injured mice spent significantly less time. Correlation coefficients between NOR and CA1, CA2/3, and DG neuronal cell counts, were 0.91, 0.91, and 0.80, respectively.…”

Substance P: A Novel Target in the Treatment of Cerebral Oedema and Elevated Intracranial Pressure Following Traumatic Brain Injury

“…Such alterations in vascular permeability were also associated with the development of cerebral oedema of the vasogenic type [12]. Persistent functional deficits, both motor and cognitive, were also observed in the setting of neurogenic inflammation following TBI [12,32]. More recently, a role for neurogenic inflammation in BBB dysfunction, cerebral oedema, and functional deficits has been described in stroke [34][35][36]38].…”

“…Originally described in peripheral tissues, it is now known that neurogenic inflammation occurs in the brain following injury [12,[32][33][34][35][36][37][38]. In stroke, Stumm and colleagues (2002) proposed that activation of NK1 tachykinin receptors on vascular endothelium may contribute to cerebral oedema [39].…”

“…An NK1 tachykinin receptor antagonist administered at 30mins following trauma conferred protection from injury-induced BBB permeability alterations, cerebral oedema ( Figure 2) and functional deficits [12] in rodent models. Moreover, the therapeutic window was shown to be at least 12h following trauma with improvements in neurological outcome and a reduction in neuronal injury still observed with such delayed treatment [32]. Studies using capsaicin pre-treatment to deplete the neuropeptides before injury have produced comparable improvements in BBB status, cerebral oedema and neurological outcome [33].…”

Mineralizing angiopathy and minor head trauma

“…3,4 These may lead to changes in brain perfusion, mediated through autonomic and trigeminovascular responses. 5 deVeber proposes that mineralized arteries would be more rigid than normal vessels and predisposed to shear injury.…”