Spinal cord injury (SCI) disrupts critical physiological systems, including the cardiovascular and immune system. Plasticity of spinal circuits below the injury results in abnormal, heightened sympathetic responses, such as extreme, sudden hypertension that hallmarks life-threatening autonomic dysreflexia. Moreover, such sympathetic hyperreflexia detrimentally impacts other effector organs, including the spleen, resulting in spinal cord injury-induced immunodeficiency. Consequently, infection is a leading cause of mortality after SCI. Unfortunately, there are no current treatments that prophylactically limit sympathetic hyperreflexia to prevent subsequent effector organ dysfunction. The cytokine soluble tumor necrosis factor ␣ (sTNF␣) is upregulated in the CNS within minutes after SCI and remains elevated. Here, we report that commencing intrathecal administration of XPro1595, an inhibitor of sTNF␣, at a clinically feasible, postinjury time point (i.e., 3 d after complete SCI) sufficiently diminishes maladaptive plasticity within the spinal sympathetic reflex circuit. This results in less severe autonomic dysreflexia, a real-time gauge of sympathetic hyperreflexia, for months postinjury. Remarkably, delayed delivery of the sTNF␣ inhibitor prevents sympathetic hyperreflexia-associated splenic atrophy and loss of leukocytes to dramatically improve the endogenous ability of chronic SCI rats to fight off pneumonia, a common cause of hospitalization after injury. The improved immune function with XPro1595 correlates with less noradrenergic fiber sprouting and normalized norepinephrine levels in the spleen, indicating that heightened, central sTNF␣ signaling drives peripheral, norepinephrine-mediated organ dysfunction, a novel mechanism of action. Thus, our preclinical study supports intrathecally targeting sTNF␣ as a viable strategy to broadly attenuate sympathetic dysregulation, thereby improving cardiovascular regulation and immunity long after SCI.
Chronic or repeated exposure to stressful stimuli can result in several maladaptive consequences, including increased anxiety-like behaviors and altered peptide expression in anxiety-related brain structures. Among these structures, the bed nucleus of the stria terminalis (BNST) has been implicated in emotional behaviors as well as regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. In male rodents, chronic variate stress (CVS) has been shown to increase BNST pituitary adenylate cyclase activating polypeptide (PACAP) and its cognate PAC1 receptor transcript, and BNST PACAP signaling may mediate the maladaptive changes associated with chronic stress. Here, we examined whether CVS would sensitize the behavioral and/or endocrine response to a subthreshold BNST PACAP infusion. Male and cycling female rats were exposed to a 7 day CVS paradigm previously shown to upregulate BNST PAC1 receptor transcripts; control rats were not stressed. Twenty-four hours following the last stressor, rats were bilaterally infused into the BNST with a normally subthreshold dose of PACAP. We found an increase in startle amplitude and plasma corticosterone levels 30 min following intra-BNST PACAP infusion in male rats that had been previously exposed to CVS. CVS did not enhance the startle response in cycling females. Equimolar infusion of the VPAC1/2 receptor ligand vasoactive intestinal polypeptide (VIP) had no effect on plasma corticosterone levels even in previously stressed male rats. These results suggest that repeated exposure to stressors may differentially alter the neural circuits underlying the responses to intra-BNST PACAP, and may result in different anxiety-like responses in males and females.
Following an injury to the central nervous system (CNS), spontaneous plasticity is observed throughout the neuraxis and affects multiple key circuits. Much of this spontaneous plasticity can elicit beneficial and deleterious functional outcomes, depending on the context of plasticity and circuit affected. Injury-induced activation of the neuroimmune system has been proposed to be a major factor in driving this plasticity, as neuroimmune and inflammatory factors have been shown to influence cellular, synaptic, structural, and anatomical plasticity. Here, we will review the mechanisms through which the neuroimmune system mediates plasticity after CNS injury. Understanding the role of specific neuroimmune factors in driving adaptive and maladaptive plasticity may offer valuable therapeutic insight into how to promote adaptive plasticity and/or diminish maladaptive plasticity, respectively.
-The aim was to determine the role CGRP and/or tachykinins released from sensory neural mechanisms in enteric neural vasodilator pathways. These pathways project through the myenteric plexus to submucosal vasodilator neurons. Submucosal arterioles were exposed in the distal portion of an in vitro combined submucosal-myenteric guinea pig ileal preparation, and dilation was monitored with videomicroscopy. Vasodilator neural reflexes were activated by gently stroking the mucosa with a fine brush or by distending a balloon placed beneath the flat-sheet preparation in the proximal portion. Dilations evoked by mucosal stroking were inhibited 64% by the CGRP 8 -37 and 37% by NK 3 (SR 142801) antagonists. When the two antagonists were combined with hexamethonium, only a small vasodilation persisted. Balloon distensionevoked vasodilations were inhibited by NK 3 antagonists (66%) but were not altered by CGRP 8 -37. In preparations in which myenteric descending interneurons were directly activated by electrical stimulation, combined application of CGRP 8 -37 and the NK antagonists had no effect. Stimulation of capsaicin sensitive nerves in the myenteric plexus did not activate these vasodilator reflexes. These findings suggest that mucosal-activated reflexes result from the release of CGRP and tachykinins from enteric sensory neurons. Distensionevoked responses were significantly blocked by NK 3 antagonists, suggesting that stretch activation of myenteric sensory neurons release tachykinins that activate NK 3 receptors on myenteric vasodilator pathways.intrinsic primary afferent neuron; vasodilation; submucosal plexus; submucosal arterioles; tachykinins; calcitonin gene-related peptide NEURAL REFLEXES REGULATING gastrointestinal function are mediated by neural pathways that project within and extrinsic to the intestine (5). The intrinsic neural pathways project within the enteric nervous system, providing an important mechanism for precise regulation of intestinal function. This includes motility (8, 34), secretion (2), and blood flow (16), which respond to changes within the lumen and the wall of the intestine. Although the neural components of these reflexes, sensory or intrinsic primary afferent neurons (IPANS), interneurons, and motoneurons, have been characterized in detail in the past few decades, the enteric reflexes regulating blood flow have received relatively less attention (5). Studies have shown that submucosal cholinergic vasodilator neurons are the motoneurons innervating the submucosal arterioles (21), the final resistance vessels controlling mucosal blood flow (9), but little is known about the sensory mechanisms that activate these motoneurons.IPANs are the first neurons in intrinsic reflexes (5, 6), and several neurotransmitters have been implicated in their actions (5,6,11,22). These neurons exhibit choline acetyl transferase and substance P immunoreactivity in guinea pig (5) and CGRP immunoreactivity in the mouse (7). NK 3 receptors are found on most myenteric interneurons and IPANs (15). Their activat...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.