Blocking Neurogenic Inflammation for the Treatment of Acute Disorders of the Central Nervous System

Abstract

Classical inflammation is a well-characterized secondary response to many acute disorders of the central nervous system. However, in recent years, the role of neurogenic inflammation in the pathogenesis of neurological diseases has gained increasing attention, with a particular focus on its effects on modulation of the blood-brain barrier BBB. The neuropeptide substance P has been shown to increase blood-brain barrier permeability following acute injury to the brain and is associated with marked cerebral edema. Its release has also been shown to modulate classical inflammation. Accordingly, blocking substance P NK1 receptors may provide a novel alternative treatment to ameliorate the deleterious effects of neurogenic inflammation in the central nervous system. The purpose of this paper is to provide an overview of the role of substance P and neurogenic inflammation in acute injury to the central nervous system following traumatic brain injury, spinal cord injury, stroke, and meningitis.

Chronic Neurodegeneration After Traumatic Brain Injury: Alzheimer Disease, Chronic Traumatic Encephalopathy, or Persistent Neuroinflammation?

“…Indeed, many neuroprotective strategies have been directed at such inflammation or related factors [81][82][83][84]. Also well established, but less well appreciated is that clinical TBI can cause persistent microglial activation [34,37,38,[85][86][87], and that such chronic inflammation may contribute to neurodegeneration.…”

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

“…SP plays a major pathogenic role as it is an important mediator of both inflammation and increased blood-brain barrier (BBB) permeability in the CNS 10 . In addition, SP is a potent initiator of neurogenic inflammation, which differs from classical inflammation in that it is neurally elicited and results in vasodilation, plasma extravasation, tissue swelling, mast cell degranulation, and increased permeability of the BBB through the release of neuropeptides 4,11 . In this context, SP is increasingly being recognized as an important element in the pathogenesis of many neurological diseases.…”

“…Once released, SP may have direct post-synaptic actions as a neurotransmitter, modulatory function at post-synaptic sites, or other functions on nonneuronal targets 11,14 . The major pathways activated by the SP/NK1R complex lead to phosphoinositide hydrolysis, calcium mobilization, and mitogen-activated protein kinase (MAPK) activation 15,16 .…”

“…Fosaprepitant (Emend for injection), a water-soluble phosphoryl prodrug for intravenous use, is also available and is marketed as Ivemend 57 . These drugs are well tolerated and used as antiemetics to combat chemotherapy-induced nausea in cancer patients 11 . Investigators have focused on the use of NK1R antagonists as an alternative to classical anti-inflammatory drugs.…”

Batroxobin protects against spinal cord injury in rats by promoting the expression of vascular endothelial growth factor to reduce apoptosis

“…The apoptotic cell death of both neurons and oligodendrocytes may therefore be a causative factor contributing to the paralysis of patients with SCI (7,8). Therapeutic interventions using neurotrophic factors have focused on the prevention of such reactions to reduce cell death and promote tissue regeneration (9).…”