Acute post-injury blockade of α2δ-1 calcium channel subunits prevents pathological autonomic plasticity after spinal cord injury

Brennan, Faith H.; Noble, Benjamin T.; Wang, Yan; Guan, Zhen; Davis, Hayes; Mo, Xiaokui; Harris, Clay; Eroğlu, Çağla; Ferguson, Adam R.; Popovich, Phillip G.

doi:10.1016/j.celrep.2020.108667

Cited by 28 publications

(60 citation statements)

References 85 publications

(139 reference statements)

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“…We observed that the sprouting of CGRP + fibers in the lumbar spinal cord was reduced in NMD-treated rats compared with controls. This phenomenon is similar to previous study using GBP to treat maladaptive plasticity after SCI (Brennan et al, 2021), however, the detailed mechanisms that both drugs inhibit CGRP + sensory fiber growth remain to be investigated. We noted that the Von Frey test was not significant different between the two groups at week 8 but was prior and afterwards.…”

Section: Discussionsupporting

confidence: 89%

Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Guo

Zheng

et al. 2021

Front. Pharmacol.

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Spinal cord injury (SCI) is a devastating condition that results in severe motor, sensory, and autonomic dysfunction. The L-/T-type calcium channel blocker nimodipine (NMD) exerts a protective effect on neuronal injury; however, the protective effects of long-term administration of NMD in subjects with SCI remain unknown. Thus, the aim of this study was to evaluate the role of long-term treatment with NMD on a clinically relevant SCI model. Female rats with SCI induced by 25 mm contusion were subcutaneously injected with vehicle or 10 mg/kg NMD daily for six consecutive weeks. We monitored the motor score, hind limb grip strength, pain-related behaviors, and bladder function in this study to assess the efficacy of NMD in rats with SCI. Rats treated with NMD showed improvements in locomotion, pain-related behaviors, and spasticity-like symptoms, but not in open-field spontaneous activity, hind limb grip strength or bladder function. SCI lesion areas and perilesional neuronal numbers, gliosis and calcitonin gene-related peptide (CGRP+) fiber sprouting in the lumbar spinal cord and the expression of K+–Cl− cotransporter 2 (KCC2) on lumbar motor neurons were also observed to further explore the possible protective mechanisms of NMD. NMD-treated rats showed greater tissue preservation with reduced lesion areas and increased perilesional neuronal sparing. NMD-treated rats also showed improvements in gliosis, CGRP+ fiber sprouting in the lumbar spinal cord, and KCC2 expression in lumbar motor neurons. Together, these results indicate that long-term treatment with NMD improves functional recovery after SCI, which may provide a potential therapeutic strategy for the treatment of SCI.

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Section: Discussionsupporting

confidence: 89%

Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Guo

Zheng

et al. 2021

Front. Pharmacol.

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“…Gabapentin, a US Food and Drug Administration approved drug, has been used in the treatment of SCI for its ability to bind to the α2δ subunit to block synaptogenic excitotoxicity [ 83 ]. Specifically, it has been used to successfully attenuate spasticity [ 84 ], neuropathic pain [ 85 , 86 ], and autonomic dysreflexia [ 87 ]. Most recently, Brennan and colleagues used the human-equivalent daily dose of 1.1 gram of gabapentin as a prophylactic treatment for wildtype mice subjected to a thoracic level 3 crush injury and were successful in preventing deleterious synaptic plasticity [ 87 ].…”

Section: Therapeutic Targeting Of Microglia After Scimentioning

confidence: 99%

The Role of Microglia in Modulating Neuroinflammation after Spinal Cord Injury

Brockie

Hong

Fehlings

2021

IJMS

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The pathobiology of traumatic and nontraumatic spinal cord injury (SCI), including degenerative myelopathy, is influenced by neuroinflammation. The neuroinflammatory response is initiated by a multitude of injury signals emanating from necrotic and apoptotic cells at the lesion site, recruiting local and infiltrating immune cells that modulate inflammatory cascades to aid in the protection of the lesion site and encourage regenerative processes. While peripheral immune cells are involved, microglia, the resident immune cells of the central nervous system (CNS), are known to play a central role in modulating this response. Microglia are armed with numerous cell surface receptors that interact with neurons, astrocytes, infiltrating monocytes, and endothelial cells to facilitate a dynamic, multi-faceted injury response. While their origin and essential nature are understood, their mechanisms of action and spatial and temporal profiles warrant extensive additional research. In this review, we describe the role of microglia and the cellular network in SCI, discuss tools for their investigation, outline their spatiotemporal profile, and propose translationally-relevant therapeutic targets to modulate neuroinflammation in the setting of SCI.

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“…Gabapentin (GBP), an anti-seizure and neuropathic pain medication known to prevent synaptogenesis at high doses, has been used after SCI in preclinical models to examine its effect on AD. Several studies have indicated that acute treatment with a low-dose of GBP (50 mg/kg) or chronic treatment with a very high-dose of GBP (400 mg/kg/day) starting the day of complete T4 SCI in rats decreased mean arterial pressure in response to CRD [ 134 , 135 , 136 , 137 ]. However, chronic treatment with this very high-dose of GBP (400 mg/kg/day) also increased the frequency of spontaneous AD events [ 136 ].…”

Section: Potential Interventions To Improve Immunological Function Post-scimentioning

confidence: 99%

“…On the other hand, in another recent study, chronic treatment with a slightly lower dose of GBP (200 mg/kg/day) starting one day after complete T4 SCI in mice prevented excitatory synaptic formation and sprouting of sensory afferents, two examples of spinal plasticity associated with sympathetic hyperreflexia. This resulted in reduced frequency of spontaneous AD events, attenuated induced AD by CRD, and, importantly, mitigated changes in immune profile after SCI ( Figure 3 ) [ 137 ]. Additionally, chronic treatment with this dose of GBP resulted in prevention of splenic atrophy and maintenance of CD3 + T cell and B220 + B cell populations in the spleen ( Figure 3 ) [ 137 ].…”

Section: Potential Interventions To Improve Immunological Function Post-scimentioning

confidence: 99%

“…This resulted in reduced frequency of spontaneous AD events, attenuated induced AD by CRD, and, importantly, mitigated changes in immune profile after SCI ( Figure 3 ) [ 137 ]. Additionally, chronic treatment with this dose of GBP resulted in prevention of splenic atrophy and maintenance of CD3 + T cell and B220 + B cell populations in the spleen ( Figure 3 ) [ 137 ]. One important difference in these seemingly conflicting studies is that Eldahan et al did not observe any changes in excitatory or inhibitory presynaptic markers in the lumbosacral dorsal horn at the very high dose of GBP.…”

Section: Potential Interventions To Improve Immunological Function Post-scimentioning

confidence: 99%

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Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury

Jeffries

Tom

2021

Biology

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Individuals with spinal cord injuries (SCI) exhibit increased susceptibility to infection, with pneumonia consistently ranking as a leading cause of death. Despite this statistic, chronic inflammation and concurrent immune suppression have only recently begun to be explored mechanistically. Investigators have now identified numerous changes that occur in the peripheral immune system post-SCI, including splenic atrophy, reduced circulating lymphocytes, and impaired lymphocyte function. These effects stem from maladaptive changes in the spinal cord after injury, including plasticity within the spinal sympathetic reflex circuit that results in exaggerated sympathetic output in response to peripheral stimulation below injury level. Such pathological activity is particularly evident after a severe high-level injury above thoracic spinal cord segment 6, greatly increasing the risk of the development of sympathetic hyperreflexia and subsequent disrupted regulation of lymphoid organs. Encouragingly, studies have presented evidence for promising therapies, such as modulation of neuroimmune activity, to improve regulation of peripheral immune function. In this review, we summarize recent publications examining (1) how various immune functions and populations are affected, (2) mechanisms behind SCI-induced immune dysfunction, and (3) potential interventions to improve SCI individuals’ immunological function to strengthen resistance to potentially deadly infections.

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Acute post-injury blockade of α2δ-1 calcium channel subunits prevents pathological autonomic plasticity after spinal cord injury

Cited by 28 publications

References 85 publications

Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

The Role of Microglia in Modulating Neuroinflammation after Spinal Cord Injury

Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury

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