Acute Post-Injury Blockade of α2δ-1 Receptors 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; Popovich, Phillip G.

doi:10.2139/ssrn.3470401

Cited by 2 publications

(5 citation statements)

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“…Finally, a recent study (Brennan et al, 2020) shows that prophylactic treatment with gabapentin in an animal model of spinal cord injury prevents plasticity in spinal autonomic circuits that cause autonomic dysreflexia by preventing thrombospondin-induced changes. Each of these processes appear to activate astrocytes and strengthen nearby glutamate synapses in a process that is blocked by gabapentinoid drugs.…”

Section: Jpet # 266056 Page 21mentioning

confidence: 99%

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Taylor¹,

Harris²

2020

J Pharmacol Exp Ther

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The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, 2-1 or CaVa2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The 2-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that 2-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDAsensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to 2-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. Significance Statement It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the 2-1 protein. However, recent findings show that the 2-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.

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Section: Jpet # 266056 Page 21mentioning

confidence: 99%

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Taylor¹,

Harris²

2020

J Pharmacol Exp Ther

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“…From the animal literature, the duration of dosing ranged from 14 to 131 days post-SCI, with the average across studies being 52 days (4,14,15,56). In humans, spinal shock typically ends, and early hyperreflexia emerges by 1-month post injury, with late hyperreflexia emerging between 1 and 12 months' postinjury (57).…”

Section: Rationale For Duration Of Treatmentmentioning

confidence: 99%

“…Daily administration of low-dose (human equivalent dose of 648 mg/day) gabapentin for the first four weeks post-SCI in rats further suggests a role in mitigating evoked AD (14); high-dose (human equivalent dose of 5,184 mg/day) gabapentin did not have this effect (14). Additionally, it was recently demonstrated in a mouse model that daily administration of a low-medium dose (human equivalent dose of 1,296 mg/day) of gabapentin for 5 weeks post-SCI resulted in the blockade of excitatory synaptogenesis and sprouting of autonomic fibers innervating immune organs as well as nociceptive fibers that trigger AD (4). Functionally, this was correlated with a reduction in the frequency of spontaneous AD and severity of evoked AD as well as protection from SCI-induced immune suppression, which persisted for a month after stopping gabapentin (4).…”

Section: Introductionmentioning

confidence: 99%

“…It is thought that this analgesic mechanism is a result of astrocyte-derived thrombospondins promoting excitatory synapse formation via α2δ1 subunits (3). Although gabapentin has only two FDA-approved indications, it has been prescribed off-label for many years for multiple reasons, including management of neuropathic pain in spinal cord injury (SCI) (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, it was recently demonstrated in a mouse model that daily administration of a low-medium dose (human equivalent dose of 1,296 mg/day) of gabapentin for 5 weeks post-SCI resulted in the blockade of excitatory synaptogenesis and sprouting of autonomic fibers innervating immune organs as well as nociceptive fibers that trigger AD (4). Functionally, this was correlated with a reduction in the frequency of spontaneous AD and severity of evoked AD as well as protection from SCI-induced immune suppression, which persisted for a month after stopping gabapentin (4). Daily administration of low-dose (human equivalent dose of 648 mg/day) gabapentin, started early after C5 hemisection in mice and continued for 4 months, has also been demonstrated to lead to sprouting of corticospinal tract fibers and improvement in forelimb function (15).…”

Section: Introductionmentioning

confidence: 99%

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Feasibility of gabapentin as an intervention for neurorecovery after an acute spinal cord injury: Protocol

et al. 2022

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IntroductionThis protocol is describing the first ever prospective, mock-efficacy, dose exploration trial design testing the feasibility of administering gabapentin in the acute setting as an intervention for neurorecovery. Gabapentin is an FDA-approved medication for treating seizures and postherpetic neuralgia and is used broadly off-label for neuropathic pain management for many conditions, including spinal cord injury. Emerging data suggests that when given early after spinal cord injury onset and in low-medium doses, gabapentin may have properties that promote recovery of neurological function. The objective of this trial is to assess the feasibility of conducting an efficacy trial in which gabapentin is started early after injury, is restricted in its dose, and is not used for pain management.Methods and analysisForty-two people aged 18 years or older with any level and any severity of spinal cord injury induced by a trauma will be enrolled, randomized, and have the first dose of study medication by 120 h post-injury onset. Participants will be randomly assigned to one of three groups: 600, 1,800 mg/day gabapentin, or placebo. Study medication will be given for a 90-day duration. Blinded assessments will be obtained at 7 days post-injury (baseline), 30 days post-injury (interim), after the 90-day treatment duration/approximately 3 months post-injury (end of treatment), and at 6 months post-injury (end of study). The key analysis parameters will evaluate feasibility of recruitment of target population, delivery of drug treatment protocol, maintenance of blinding, and retention of participants.DiscussionOutputs from this trial will inform research and clinical practice on the effects of manipulating gabapentin for non-pain management purposes in the acute setting and will guide the development of a properly powered efficacy trial of gabapentin as an intervention for neurorecovery in spinal cord injury.Ethics and disseminationThe study was approved by the MetroHealth Institutional Review Board (IRB21-00609) and registered at clinicaltrials.gov prior to enrolling any participants. Dissemination will include peer-reviewed publications, presentations at professional conferences and in the community, and through other healthcare and public venues.Clinical trial registrationwww.ClinicalTrials.gov, identifier: NCT05302999; protocol version 1.1 approved 05/23/2022.Trial fundingNational Institute on Disability, Independent Living and Rehabilitation Research.

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Acute Post-Injury Blockade of α2δ-1 Receptors Prevents Pathological Autonomic Plasticity after Spinal Cord Injury

Cited by 2 publications

References 0 publications

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Feasibility of gabapentin as an intervention for neurorecovery after an acute spinal cord injury: Protocol

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