The Role of Neurogenic Inflammation in Blood-Brain Barrier Disruption and Development of Cerebral Oedema Following Acute Central Nervous System (CNS) Injury

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.

Innervation is higher above Bone Remodeling Surfaces and in Cortical Pores in Human Bone: Lessons from patients with primary hyperparathyroidism

“…bone-remodeling compartment (BRC) canopy, above remodeling sites 73,74 . Here the permeability may be neuronally regulated in the same way as the regulation of blood-brain barrier permeability by CGRP and Substance P following neuronal inflammation in the central nervous system 75,76 .…”

Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke

“…BBB breakdown leads to cerebral oedema [ 96 , 97 ] and haemorrhagic transformation [ 98 , 99 ], which are common complications of ischemic stroke that can impact the outcomes of these patients with potentially serious and life-threatening consequences [ 100 ]. BBB breakdown is the main cause of vasogenic oedema, where water and plasma proteins enter the brain interstitial space, leading to brain tissue swelling as the brain capillaries behave like fenestrated capillaries.…”

The Protective Role of Immunomodulators on Tissue-Type Plasminogen Activator-Induced Hemorrhagic Transformation in Experimental Stroke: A Systematic Review and Meta-Analysis

“…Blood brain-barrier (BBB) damage is the most critical factor in the pathogenesis of HT. Although the mechanism underlying BBB damage is not fully understood, excessive neuroinflammation is thought to be involved in the process (Sorby-Adams et al, 2017). Therefore, immunomodulation seems like a promising direction of drug development for tPA-associated HT.…”