Substance P in traumatic brain injury

Thesis (M.S.) -- University of Adelaide, Dept. of Pathology, 200

Expanding the role of tachykinins in the neuroendocrine control of reproduction

Reproductive function is driven by the hormonal interplay between the gonads and brain–pituitary axis. Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner, which is critical for the attainment and maintenance of fertility; however, GnRH neurons lack the ability to directly respond to most regulatory factors, and a hierarchical upstream neuronal network governs its secretion. We and others proposed a model in which Kiss1 neurons in the arcuate nucleus (ARC), called as KNDy neurons, release kisspeptin (a potent GnRH secretagogue) in a pulsatile manner to drive GnRH pulses under the coordinated autosynaptic action of its cotransmitters, the tachykinin neurokinin B (NKB, stimulatory) and dynorphin (inhibitory). Numerous genetic and pharmacological studies support this model; however, additional regulatory mechanisms (upstream of KNDy neurons) and alternative pathways of GnRH secretion (kisspeptin independent) exist, but remain ill defined. In this aspect, attention to other members of the tachykinin family, namely substance P (SP) and neurokinin A (NKA), has recently been rekindled. Even though there are still major gaps in our knowledge about the functional significance of these systems, substantial evidence, as discussed below, is placing tachykinin signaling as an important pathway for the awakening of the reproductive axis and the onset of puberty to physiological GnRH secretion and maintenance of fertility in adulthood

The role of substance P in secondary pathophysiology after traumatic brain injury

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.Robert Vink, Levon Gabrielian and Emma Thornto

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Inflammation in acute CNS injury: a focus on the role of substance P

Recently, a number of reports have shown that neurogenic inflammation may play a role in the secondary injury response following acute injury to the CNS, including traumatic brain injury (TBI) and stroke. In particular substance P (SP) release appears to be critically involved. Specifically, the expression of the neuropeptide SP is increased in acute CNS injury, with the magnitude of SP release being related to both the frequency and magnitude of the insult. SP release is associated with an increase in blood-brain barrier permeability and the development of vasogenic oedema as well as neuronal injury and worse functional outcome. Moreover, inhibiting the actions of SP through use of a NK1 receptor antagonist is highly beneficial in both focal and diffuse models of TBI, as well as in ischaemic stroke, with a therapeutic window of up to 12 h. We propose that NK1 receptor antagonists represent a novel therapeutic option for treatment of neurogenic inflammation following acute CNS injury.F Corrigan, R Vink, and R J Turne

Studies on blood bradykinin in man

[Typescript]210 p.Thesis -- University of Adelaide, Dept. of Medicine, 196