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

Abstract

Summary:Although a number of secondary injury factors are known to contribute to the development of morphological injury and functional deficits following traumatic brain injury, accumulating evidence has suggested that neuropeptides, and in particular substance P, may play a critical role. Substance P is released early following acute injury to the CNS as part of a neurogenic inflammatory response. In so doing, it facilitates an increase in the permeability of the bloodbrain barrier and the development of vasogenic edema. At the cellular level, substance P has been shown to directly result in neuronal cell death; functionally, substance P has been implicated in learning and memory, mood and anxiety, stress mechanisms, emotion-processing, migraine, emesis, pain, and seizures, all of which may be adversely affected after brain injury. Inhibition of post-traumatic substance P activity, either by preventing release or by antagonism of the neurokinin-1 receptor, has consistently resulted in a profound decrease in development of edema and marked improvements in functional outcome. This review summarizes the current evidence supporting a role for substance P in acute brain injury.

Expanding the role of tachykinins in the neuroendocrine control of reproduction

“…The reason for this is not known; however, it may reflect a species difference. Interestingly, supporting the role of SP in the central control of puberty onset is the fact that higher SP levels detected in the brain of patients after traumatic brain injury (Vink & van den Heuvel 2010, Zacest et al 2010, Gabrielian et al 2013) correlate with the significantly higher ratio of children displaying precocious puberty after traumatic brain injury (Blendonohy & Philip 1991, Kaulfers et al 2010. Overall, these data suggest a greater sensitivity to hypothalamic SP (and possibly NKA), at the time of puberty initiation, presumably contributing to an increase in GnRH pulses and activation of the gonadotropic axis; however, despite the compelling evidence for a central role of SP, we cannot rule out the possibility of actions of SP in other organs of the gonadotropic axis, such as the ovary (Debeljuk 2003(Debeljuk , 2006.…”

Magnesium in Man: Implications for Health and Disease

“…Reduced CSF Mg 2ϩ levels increase oxidative stress (ROS, NO) and lipid peroxidation, which both contribute to the severity of TBI (77,416). Additionally, it has been proposed that Mg 2ϩ deficiency increases the release of substance P in TBI, resulting in neuronal cell death and edema (539). In animal experiments, Mg 2ϩ improved sensorimotor/motor function as well as cognitive function (233).…”

Acute Effects of a Selective Cannabinoid-2 Receptor Agonist on Neuroinflammation in a Model of Traumatic Brain Injury

“…Cerebral edema formation is due in part to neurogenic inflammatory mechanisms in which the release of substance P, a potent long-lasting vasoactive tachykinin, is believed to be the predominant mediator (Donkin et al, 2007(Donkin et al, , 2009. Substance P antagonists are currently proposed as a therapeutic approach for TBI (Vink and van den Heuvel, 2010). However, in a rat model of sciatic nerve section, an unfortunate side effect of 2 weeks of treatment with an antagonist against the key substance P receptor (neurokinin-1) is widespread bone resorption (Kingery et al, 2003).…”