Abstract
It has recently been shown that substance P (SP) plays a major role in the secondary injury process following traumatic brain injury (TBI), particularly with respect to neuroinflammation, increased blood–brain barrier (BBB) permeability, and edema formation. Edema formation is associated with the development of increased intracranial pressure (ICP) that has been widely associated with increased mortality and morbidity after neurotrauma. However, a pharmacological intervention to specifically reduce ICP is yet to be developed, with current interventions limited to osmotic therapy rather than addressing the cause of increased ICP. Given that previous publications have shown that SP, NK1 receptor antagonists reduce edema after TBI, more recent studies have examined whether these compounds might also reduce ICP and improve brain oxygenation after TBI. We discuss the results of these studies, which demonstrate that NK1 antagonists reduce posttraumatic ICP to near normal levels within 4 h of drug administration, as well as restoring brain oxygenation to near normal levels in the same time frame. The improvements in these parameters occurred in association with an improvement in BBB integrity to serum proteins, suggesting that SP-mediated increases in vascular permeability significantly contribute to the development of increased ICP after acute brain injury. NK1 antagonists may therefore provide a novel, mechanistically targeted approach to the management of increased ICP.
Highlights
Reviewed by: Fredrik Clausen, Uppsala University, Sweden David J
It has recently been shown that substance P (SP) plays a major role in the secondary injury process following traumatic brain injury (TBI), with respect to neuroinflammation, increased blood–brain barrier (BBB) permeability, and edema formation
Edema formation is associated with the development of increased intracranial pressure (ICP) that has been widely associated with increased mortality and morbidity after neurotrauma
Summary
Substance P is peptide of 11 amino acids and belongs to the large tachykinin peptide family containing over 40 tachykinins, including neurokinin A, neurokinin B, neuropeptide-γ (NPγ), and the recently identified hemokinin 1. SP can bind to tachykinin NK receptors to exert direct postsynaptic actions as a neurotransmitter or modulate other non-neuronal targets [22]. The mRNA encoding the tachykinin is initially translated into a larger protein precursor from which SP is subsequently released by the actions of proteases called convertases. The individual cellular localization of NEP and/or ACE suggests that these enzymes are most likely responsible for the in vivo cleavage of SP [36], albeit that all of these enzymes have been shown to cleave the tachykinin in vitro. NEP hydrolyzes SP in the peripheral tissues, brain, and spinal cord [37,38,39] with ACE-degrading SP in the plasma, CSF, and the substantia nigra [40], as well as contributing to the degradation of peptide fragments released by NEP. During noxious stimulation or neurogenic inflammation in the periphery, there is an upregulation [28] of PPT mRNA expression [52] and NK1 receptor mRNA [53]
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