Failure of Ischemic Neuroprotection by Potentiators of Gamma-aminobutyric Acid

Madden, Kenneth P.; Clark, Wayne M.; Lessov, Nicola

doi:10.3121/cmr.1.2.119

Cited by 7 publications

(8 citation statements)

References 47 publications

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“…Increasing GABA signalling in post stroke patients and rodent models does not improve motor function16. Rather, administering a benzodiazepine after rehabilitation leads to an acute loss of the regained function2474.…”

Section: Discussionmentioning

confidence: 99%

“…The GABAergic system and the extracellular matrix could have an important role in controlling plastic phenomena16. For example, Perineuronal Nets (PNNs), preferentially surrounding the soma of fast-spiking parvalbumin-positive interneurons17, and the GABAergic system have been extensively investigated during the maturation and plasticity of the visual system181920.…”

mentioning

confidence: 99%

“…Moreover, following CNS injury, the degradation of PNNs promotes sensory-motor recovery212223. Increasing GABAergic signalling after stroke is not effective at improving motor performances16, but rather produces a worsening of recovered function in stroke patients24. Conversely, a reduced GABAergic inhibition is associated with functional recovery252627.…”

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confidence: 99%

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Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice

Alia

Spalletti

Lai

et al. 2016

Sci Rep

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A deeper understanding of post-stroke plasticity is critical to devise more effective pharmacological and rehabilitative treatments. The GABAergic system is one of the key modulators of neuronal plasticity, and plays an important role in the control of “critical periods” during brain development. Here, we report a key role for GABAergic inhibition in functional restoration following ischemia in the adult mouse forelimb motor cortex. After stroke, the majority of cortical sites in peri-infarct areas evoked simultaneous movements of forelimb, hindlimb and tail, consistent with a loss of inhibitory signalling. Accordingly, we found a delayed decrease in several GABAergic markers that accompanied cortical reorganization. To test whether reductions in GABAergic signalling were causally involved in motor improvements, we treated animals during an early post-stroke period with a benzodiazepine inverse agonist, which impairs GABAA receptor function. We found that hampering GABAA signalling led to significant restoration of function in general motor tests (i.e., gridwalk and pellet reaching tasks), with no significant impact on the kinematics of reaching movements. Improvements were persistent as they remained detectable about three weeks after treatment. These data demonstrate a key role for GABAergic inhibition in limiting motor improvements after cortical stroke.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice

Alia

Spalletti

Lai

et al. 2016

Sci Rep

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“…Although in vitro studies of topiramate and lamotrigine have suggested a neuroprotective effect 29 , in vivo studies were generally negative in various models of focal cerebral ischemia 18-22 . All studies, however, have tested single doses or short-term treatment administered before or after ischemia onset.…”

Section: Discussionmentioning

confidence: 99%

“…We tested lamotrigine because it also inhibits SD upon chronic treatment in rats 16 , although its efficacy in migraine is not proven 17 . Both drugs have been studied previously in experimental focal ischemia models without consistent efficacy, albeit as a single dose or as short-term post-ischemic dosing 18-22 . Therefore, neither drug has been tested as a prophylactic intervention in stroke.…”

Section: Introductionmentioning

confidence: 99%

Migraine Prophylaxis, Ischemic Depolarizations, and Stroke Outcomes in Mice

Eikermann-Haerter

Lee

Yalcin

et al. 2015

Stroke

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Background and Purpose Migraine with aura is an established stroke risk factor, and excitatory mechanisms such as spreading depression are implicated in the pathogenesis of both migraine and stroke. Spontaneous spreading depression waves originate within the peri-infarct tissue and exacerbate the metabolic mismatch during focal cerebral ischemia. Genetically enhanced spreading depression susceptibility facilitates anoxic depolarizations and peri-infarct spreading depressions and accelerates infarct growth, suggesting that susceptibility to spreading depression is a critical determinant of vulnerability to ischemic injury. Because chronic treatment with migraine prophylactic drugs suppresses spreading depression susceptibility, we tested whether migraine prophylaxis can also suppress ischemic depolarizations and improve stroke outcome. Methods We measured the cortical susceptibility to spreading depression and ischemic depolarizations, and determined tissue and neurological outcome after middle cerebral artery occlusion in wild type and familial hemiplegic migraine type 1 knock-in mice treated with vehicle, topiramate or lamotrigine daily for 7 weeks or as a single dose shortly before testing. Results Chronic treatment with topiramate or lamotrigine reduces the susceptibility to KCl- or electrical stimulation-induced spreading depressions as well as ischemic depolarizations in both wild-type and familial hemiplegic migraine type 1 mutant mice. Consequently, both tissue and neurological outcomes are improved. Notably, treatment with a single dose of either drug is ineffective. Conclusions These data underscore the importance of hyperexcitability as a mechanism for increased stroke risk in migraineurs, and suggest that migraine prophylaxis may not only prevent migraine attacks but also protect migraineurs against ischemic injury.

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