Riluzole attenuates neuropathic pain and enhances functional recovery in a rodent model of cervical spondylotic myelopathy

Moon, Eun Su; Karadimas, Spyridon K.; Yu, Wen-Ru; Austin, James W.; Fehlings, Michael G.

doi:10.1016/j.nbd.2013.10.020

Cited by 66 publications

(73 citation statements)

References 58 publications

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“…33 Moreover, work from our lab has shown that print intensity can be used as an indicator of neuropathic pain in a rodent model of cervical spondylotic myelopathy. 20 Our data support the presence of neuropathic pain based on decreased print intensity in both the fore-and hindpaws. Further, these parameters decline over time, which is consistent with previous work in a rat model of clip compression that showed that neuropathic pain becomes pronounced 3-4 weeks post-SCI.…”

Section: Discussionsupporting

confidence: 80%

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Bilateral Contusion-Compression Model of Incomplete Traumatic Cervical Spinal Cord Injury

Forgione

Karadimas

Foltz

et al. 2014

Journal of Neurotrauma

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Despite the increasing incidence and prevalence of cervical spinal cord injury (cSCI), we lack clinically relevant animal models that can be used to study the pathomechanisms of this injury and test new therapies. Here, we characterize a moderate cervical contusion-compression model in rats that is similar to incomplete traumatic cSCI in humans. We characterized the effects of 18-g clip-compression injury at cervical level C6 over an 8-week recovery period. Using Luxol fast blue/hematoxylin-eosin staining in combination with quantitative stereology, we determined that 18-g injury results in loss of gray matter (GM), white matter (WM), as well as in cavity formation. Magnetization transfer and T2-weighted magnetic resonance imaging were used to analyze lesion dynamics in vivo. This analysis demonstrated that both techniques are able to differentiate between the injury epicenter, subpial rim, and WM distal to the injury. Neurobehavioral assessment of locomotor function using Basso, Beattie, and Bresnahan (BBB) scoring and CatWalk revealed limited recovery from clip-compression injury at C6. Testing of forelimb function using grip strength demonstrated significant forelimb dysfunction, similar to the loss of upper-limb motor function observed in human cSCI. Sensory-evoked potentials recorded from the forelimb and Hoffman reflex recorded from the hindlimb confirmed the fore-and hindlimb deficits observed in our neurobehavioral analysis. Here, we have characterized a clip-compression model of incomplete cSCI that closely models this condition in humans. This work directly addresses the current lack of clinically relevant models of cSCI and will thus contribute to improved success in the translation of putative therapies into the clinic.

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Section: Discussionsupporting

confidence: 80%

“…Previous work in our lab has established a methodology for using CatWalk to quantify locomotor deficits in SCI models. [18][19][20] Hindlimb swing speed was decreased by approximately 60% in C6-injured animals at 2 and 4 weeks post-injury (Fig. 5B).…”

Section: Moderate C6 Injury Results In Hind-and Forelimb Dysfunctionmentioning

confidence: 93%

Bilateral Contusion-Compression Model of Incomplete Traumatic Cervical Spinal Cord Injury

Forgione

Karadimas

Foltz

et al. 2014

Journal of Neurotrauma

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“…Key measures of coordinated 4-limb gait can be analyzed including swing speed and stride length [28]. We have previously demonstrated the utility of this tool in SCI models [29–31]. Mice were assessed at baseline and every two weeks from week 6 to 16 post-injury.…”

Section: Methodsmentioning

confidence: 99%

Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury

et al. 2017

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Traumatic spinal cord injuries (SCIs) affect millions of people worldwide; the majority of whom are in the chronic phase of their injury. Unfortunately, most current treatments target the acute/subacute injury phase as the microenvironment of chronically injured cord consists of a well-established glial scar with inhibitory chondroitin sulfate proteoglycans (CSPGs) which acts as a potent barrier to regeneration. It has been shown that CSPGs can be degraded in vivo by intrathecal Chondroitinase ABC (ChABC) to produce a more permissive environment for regeneration by endogenous cells or transplanted neural stem cells (NSCs) in the subacute phase of injury. Using a translationally-relevant clip-contusion model of cervical spinal cord injury in mice we sought to determine if ChABC pretreatment could modify the harsh chronic microenvironment to enhance subsequent regeneration by induced pluripotent stem cell-derived NSCs (iPS-NSC). Seven weeks after injury—during the chronic phase—we delivered ChABC by intrathecal osmotic pump for one week followed by intraparenchymal iPS-NSC transplant rostral and caudal to the injury epicenter. ChABC administration reduced chronic-injury scar and resulted in significantly improved iPSC-NSC survival with clear differentiation into all three neuroglial lineages. Neurons derived from transplanted cells also formed functional synapses with host circuits on patch clamp analysis. Furthermore, the combined treatment led to recovery in key functional muscle groups including forelimb grip strength and measures of forelimb/hindlimb locomotion assessed by Catwalk. This represents important proof-of-concept data that the chronically injured spinal cord can be ‘unlocked’ by ChABC pretreatment to produce a microenvironment conducive to regenerative iPS-NSC therapy.

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“…8,9 TREK-2 is also activated by arachidonic acid, lysophosphatidic acid, halothane, chloroform, riluzole, chalcones, wagonin, baicalein, 2-aminoethoxydiphenyl borate (2ABP), and ML67-33 10–17 However, while molecules such as aristolochic acid and riluzole have both been shown to reduce peripheral pain signaling, there are currently no selective TREK-2 activators. 8,18,19 Thus, it is not known whether any of these compounds exhibit their antinociceptive effects via activation of TREK-2 channels. The lack of selective TREK-2 channel activators has impeded characterization of the physiological relevance of TREK-2 in human pain sensation, as well as assessment of the therapeutic potential of activating these channels to reduce postoperative or neuropathic pain.…”

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confidence: 99%

Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx

Dadi

Vierra

Days

et al. 2016

ACS Chem. Neurosci.

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The two-pore-domain potassium (K2P) channel TREK-2 serves to modulate plasma membrane potential in dorsal root ganglia c-fiber nociceptors, which tunes electrical excitability and nociception. Thus, TREK-2 channels are considered a potential therapeutic target for treating pain; however, there are currently no selective pharmacological tools for TREK-2 channels. Here we report the identification of the first TREK-2 selective activators using a high-throughput fluorescence-based thallium (Tl+) flux screen (HTS). An initial pilot screen with a bioactive lipid library identified 11-deoxy prostaglandin F2α as a potent activator of TREK-2 channels (EC50 ≈ 0.294 µM), which was utilized to optimize the TREK-2 Tl+ flux assay (Z′ = 0.752). A HTS was then performed with 76 575 structurally diverse small molecules. Many small molecules that selectively activate TREK-2 were discovered. As these molecules were able to activate single TREK-2 channels in excised membrane patches, they are likely direct TREK-2 activators. Furthermore, TREK-2 activators reduced primary dorsal root ganglion (DRG) c-fiber Ca2+ influx. Interestingly, some of the selective TREK-2 activators such as 11-deoxy prostaglandin F2α were found to inhibit the K2P channel TREK-1. Utilizing chimeric channels containing portions of TREK-1 and TREK-2, the region of the TREK channels that allows for either small molecule activation or inhibition was identified. This region lies within the second pore domain containing extracellular loop and is predicted to play an important role in modulating TREK channel activity. Moreover, the selective TREK-2 activators identified in this HTS provide important tools for assessing human TREK-2 channel function and investigating their therapeutic potential for treating chronic pain.

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Riluzole attenuates neuropathic pain and enhances functional recovery in a rodent model of cervical spondylotic myelopathy

Cited by 66 publications

References 58 publications

Bilateral Contusion-Compression Model of Incomplete Traumatic Cervical Spinal Cord Injury

Bilateral Contusion-Compression Model of Incomplete Traumatic Cervical Spinal Cord Injury

Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury

Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx

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