The Effects of Delayed Reduction of Tonic Inhibition on Ischemic Lesion and Sensorimotor Function

Lake, Evelyn M. R.; Chaudhuri, Joydeep D.; Thomason, Lynsie A.M.; Janik, Rafal; Ganguly, Milan; Brown, Mary Elizabeth; McLaurin, JoAnne; Corbett, Dale; Stanisz, Greg J.; Stefanović, Bojana

doi:10.1038/jcbfm.2015.86

Cited by 60 publications

(56 citation statements)

References 40 publications

(84 reference statements)

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“…When this tonic inhibition is reversed with an inhibitor of GABAA α5 signaling at delayed time points there is an improvement in functional recovery of motor and sensorimotor function that is not the result of altering histologic outcome. 27, 28 Similar increases in tonic inhibition have been observed in the dentate gyrus following controlled cortical impact injury that is reversed with the GABAA α4 or δ antagonist. 29–31 Modulation of tonic inhibition may provide a novel strategy to regulate neuronal excitability and promote plasticity in networks that are altered following ischemic brain injury or TBI.…”

Section: Functional Plasticitymentioning

confidence: 65%

Neuropathophysiology of Brain Injury

Quillinan

Herson

Traystman

2016

Anesthesiology Clinics

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Every year in the United States, millions of individuals incur ischemic brain injury from stroke, cardiac arrest, or traumatic brain injury (TBI). These forms of acquired brain injury can lead to death, or in many cases long-term neurologic and neuropsychological impairments. The mechanisms of ischemic and traumatic brain injuries that lead to these deficiencies result from a complex interplay of multiple interdependent molecular pathways that include excitotoxicity, acidotoxicity, ionic imbalance, oxidative stress, inflammation, and apoptosis. This article briefly reviews several of the traditional, well-known mechanisms of brain injury and then discusses more recent developments and newer mechanisms. Although much is known concerning mechanisms of injury and the manipulation of these mechanisms to result in protection of neurons and increased behavioral performance in animal models of injury, it has been difficult to translate these effects to humans. Attention is given to why this is so and newer outcome measures of injury are discussed.

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Section: Functional Plasticitymentioning

confidence: 65%

Neuropathophysiology of Brain Injury

Quillinan

Herson

Traystman

2016

Anesthesiology Clinics

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“…Rather, administering a benzodiazepine after rehabilitation leads to an acute loss of the regained function2474. Finally, lowering tonic GABAergic inhibition improves motor recovery after stroke533. Here, we targeted GABAergic signalling by using the benzodiazepine inverse agonist DMCM, which reduces inhibitory currents by binding predominantly to synaptic GABA A receptor subunits (DMCM binding affinity α1 > α2 = α3 > α535).…”

Section: Discussionmentioning

confidence: 99%

“…A general downregulation of GABA A receptors has been found in peri-infarct areas following photothrombosis-induced lesions in rats and mice303132. Moreover, an experimental reduction of post-stroke, excessive tonic GABA signalling produces significant post-stroke improvements of forelimb function533.…”

mentioning

confidence: 99%

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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“…In stroke, tonic GABA signaling is increased in peri‐infarct cortex in a zone of cortex near the stroke site (0.2mm adjacent to the stroke) and produces a hypoexcitable state in pyramidal neurons in brain regions that normally mediate recovery of function. This can be pharmacologically reversed to enhance recovery in several rodent models of stroke at a considerable delay after the infarct 5, 47…”

Section: The Suffered Is the Learnedmentioning

confidence: 99%

Emergent properties of neural repair: elemental biology to therapeutic concepts

Carmichael

2016

Annals of Neurology

118

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Stroke is the leading cause of adult disability. The past decade has seen advances in basic science research of neural repair in stroke. The brain forms new connections after stroke, which have a causal role in recovery of function. Brain progenitors, including neuronal and glial progenitors, respond to stroke and initiate a partial formation of new neurons and glial cells. The molecular systems that underlie axonal sprouting, neurogenesis, and gliogenesis after stroke have recently been identified. Importantly, tractable drug targets exist within these molecular systems that might stimulate tissue repair. These basic science advances have taken the field to its first scientific milestone; the elemental principles of neural repair in stroke have been identified. The next stages in this field involve understanding how these elemental principles of recovery interact in the dynamic cellular systems of the repairing brain. Emergent principles arise out of the interaction of the fundamental or elemental principles in a system. In neural repair, the elemental principles of brain reorganization after stroke interact to generate higher order and distinct concepts of regenerative brain niches in cellular repair, neuronal networks in synaptic plasticity, and the distinction of molecular systems of neuroregeneration. Many of these emergent principles directly guide the development of new therapies, such as the necessity for spatial and temporal control in neural repair therapy delivery and the overlap of cancer and neural repair mechanisms. This review discusses the emergent principles of neural repair in stroke as they relate to scientific and therapeutic concepts in this field. Ann Neurol 2016;79:895–906

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The Effects of Delayed Reduction of Tonic Inhibition on Ischemic Lesion and Sensorimotor Function

Cited by 60 publications

References 40 publications

Neuropathophysiology of Brain Injury

Neuropathophysiology of Brain Injury

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

Emergent properties of neural repair: elemental biology to therapeutic concepts

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