Role of chloride cotransporters in the development of spasticity and neuropathic pain after spinal cord injury

Côté, Marie-Pascale

doi:10.1016/b978-0-12-815318-5.00018-2

Cited by 9 publications

(15 citation statements)

References 285 publications

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“…(Chen et al, 2018). While there are significant differences between the mouse and rat model (further discussed in Côté, 2020), this nevertheless suggests that restoring chloride extrusion in spinal interneurons may also contribute to functional recovery. As spinal interneurons play a role in the initiation of spasms (Bellardita et al, 2017;Lin et al, 2019), CLP257 may have affected these neurons in our study as well.…”

Section: Enhancing Kcc2 Decreases Hyperreflexia After Chronic Scimentioning

confidence: 99%

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury

Bilchak

Yeakle

Caron

et al. 2021

Experimental Neurology

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After spinal cord injury (SCI), the majority of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca 2+ -dependent signaling, current anti-spastic medications lead to serious side effects, including a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons.Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks.Increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly to restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals..

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Section: Enhancing Kcc2 Decreases Hyperreflexia After Chronic Scimentioning

confidence: 99%

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury

Bilchak

Yeakle

Caron

et al. 2021

Experimental Neurology

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“…Surprisingly, the transcript level of KCC1 was increased after SCT. KCC1 is expressed in the brain, kidney, colon, heart, red blood cells, and dorsal root ganglia [ 84 , 85 , 86 , 87 , 88 ] and is assumed to act as a housekeeping gene but also to mediate the symport of K + and Cl − ions, though a function of that transporter in MNs was not described. The increase of KCC1 may compensate for the profound decrease of KCC2 and KCC3 to protect these MNs.…”

Section: Discussionmentioning

confidence: 99%

Molecular Identification of Pro-Excitogenic Receptor and Channel Phenotypes of the Deafferented Lumbar Motoneurons in the Early Phase after SCT in Rats

Wojtaś

Skup

2022

IJMS

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Spasticity impacts the quality of life of patients suffering spinal cord injury and impedes the recovery of locomotion. At the cellular level, spasticity is considered to be primarily caused by the hyperexcitability of spinal α-motoneurons (MNs) within the spinal stretch reflex circuit. Here, we hypothesized that after a complete spinal cord transection in rats, fast adaptive molecular responses of lumbar MNs develop in return for the loss of inputs. We assumed that early loss of glutamatergic afferents changes the expression of glutamatergic AMPA and NMDA receptor subunits, which may be the forerunners of the developing spasticity of hindlimb muscles. To better understand its molecular underpinnings, concomitant expression of GABA and Glycinergic receptors and serotoninergic and noradrenergic receptors, which regulate the persistent inward currents crucial for sustained discharges in MNs, were examined together with voltage-gated ion channels and cation-chloride cotransporters. Using quantitative real-time PCR, we showed in the tracer-identified MNs innervating extensor and flexor muscles of the ankle joint multiple increases in transcripts coding for AMPAR and 5-HTR subunits, along with a profound decrease in GABAAR, GlyR subunits, and KCC2. Our study demonstrated that both MNs groups similarly adapt to a more excitable state, which may increase the occurrence of extensor and flexor muscle spasms.

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“…The 2 main cation-chloride cotransporters, NK-CC1 and KCC2, support in maintaining chloride homeostasis in the spinal cord. 53 GABAA responses in the initial developmental stage of neurons are considered excitatory, however after birth they develop and shift to produce inhibitory responses due to enhanced KCC2 expression, responsible for causing chloride extrusion. Normally, the expression of KCC2 is specifically high in neurons, whereas NKCC1 is more expressed in the respiratory system and kidneys of mice.…”

Section: Cation-chloride Cotransporters and Cnp Associationmentioning

confidence: 99%

“…GABAergic inhibitory tone in the DH is maintained typically through GABA release from interneurons that can block the nociceptive primary afferent inputs by maintaining chloride concentration. The 2 main cation-chloride cotransporters, NKCC1 and KCC2, support in maintaining chloride homeostasis in the spinal cord [ 53 ]. GABA A responses in the initial developmental stage of neurons are considered excitatory, however after birth they develop and shift to produce inhibitory responses due to enhanced KCC2 expression, responsible for causing chloride extrusion.…”

Section: Mechanisms Reducing the Gabaergic Tonementioning

confidence: 99%

Spinal Cord Injury Provoked Neuropathic Pain and Spasticity, and Their GABAergic Connection

2022

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Traumatic spinal cord injury (SCI) is the devastating neurological damage to the spinal cord that becomes more complicated in the secondary phase. The secondary injury comes with inevitable long-lasting complications, such as chronic neuropathic pain (CNP) and spasticity which interfere with day to day activities of SCI patients. Mechanisms underlying CNP post-SCI are complex and remain refractory to current medical treatment. Due to the damage, extensive inhibitory, excitatory tone dysregulation causes maladaptive synaptic transmissions, further altering the nociceptive and nonnociceptive pathways. Excitotoxicity mediated GABAergic cell loss, downregulation of glutamate acid decarboxylase enzyme, upregulation of gamma-aminobutyric acid (GABA) transporters, overactivation of glutamate receptors are some of the key evidence for hypoactive inhibitory tone contributing to CNP and spasticity post-SCI. Restoring the inhibitory GABAergic tone and preventing damage-induced excitotoxicity by employing various strategies provide neuroprotective and analgesic effects. The present article will discuss CNP and spasticity post-SCI, understanding their pathophysiological mechanisms, especially GABA-glutamate-related mechanisms, therapeutic interventions targeting them, and progress regarding how regulating the excitatory-inhibitory tone may lead to more targeted treatments for these distressing complications. Taking background knowledge of GABAergic analgesia and recent advancements, we aim to highlight how far we have reached in promoting inhibitory GABAergic tone for SCI-CNP and spasticity.

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Role of chloride cotransporters in the development of spasticity and neuropathic pain after spinal cord injury

Cited by 9 publications

References 285 publications

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury

Molecular Identification of Pro-Excitogenic Receptor and Channel Phenotypes of the Deafferented Lumbar Motoneurons in the Early Phase after SCT in Rats

Spinal Cord Injury Provoked Neuropathic Pain and Spasticity, and Their GABAergic Connection

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