Abstract
Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide, largely attributable to the development of cerebral oedema and elevated intracranial pressure (ICP). Despite this, clinical treatments are limited and new therapies are urgently required to improve patient outcomes and survival. Originally characterised in peripheral tissues, such as the skin and lungs as a neurally-elicited inflammatory process that contributes to increased microvascular permeability and tissue swelling, neurogenic inflammation has now been described in acute injury to the brain where it may play a key role in the secondary injury cascades that evolve following both TBI and stroke. In particular, release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) appear to be critically involved. In particular, increased SP expression is observed in perivascular tissue following acute CNS injury, with the magnitude of SP release being related to both the frequency and degree of the insult. SP release is associated with profound blood-brain barrier disruption and the subsequent development of vasogenic oedema, as well as neuronal injury and poor functional outcomes. Inhibition of SP through use of a neurokinin 1 (NK1) antagonist is highly beneficial following both TBI and ischaemic stroke in pre-clinical models. The role of CGRP is more unclear, especially with respect to TBI, with both elevations and reductions in CGRP levels reported following trauma. However, a beneficial role has been delineated in stroke, given its potent vasodilatory effects. Thus, modulating neuropeptides represents a novel therapeutic target in the treatment of cerebral oedema following acute CNS injury.
Highlights
Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, is a leading cause of death and disability worldwide [1,2,3]
It is clear that neurogenic inflammation is involved in enhanced permeability of the blood-brain barrier (BBB) following acute CNS injury and the subsequent development of cerebral oedema and poor outcomes
substance P (SP) is a key player in these processes with neurokinin 1 (NK1) tachykinin receptor antagonist treatment extremely effective in reducing BBB permeability, cerebral oedema and functional deficits in pre-clinical models of both TBI and stroke
Summary
Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, is a leading cause of death and disability worldwide [1,2,3]. Stroke affects in excess of 15 million people globally each year, of which six million die, and five million are left permanently disabled [3]. For those who survive the initial injury, many face long-term disability and dementia, requiring extensive rehabilitation and assistance with daily living activities [2,4]. Neurogenic inflammation has been proposed as a novel target in treating acute CNS injury. This neutrally-elicited process is characterised by the release of neuropeptides which induces vasodilation, increased microvascular permeability and tissue swelling. This review will provide an overview of studies supporting a role for neurogenic inflammation in increased blood-brain barrier (BBB) permeability, cerebral oedema formation and development of functional deficits following acute CNS injury
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