Targeted Inhibition of mGlu5 Receptors in the Contralesional Hemisphere Improves Functional Recovery After Stroke

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BACKGROUND: Understanding circuit-level changes that either enhance or impair the brain's capacity for recovery will inform the design of more specific, targeted interventions to enhance recovery from stroke. We previously reported that pharmacological blockade of mGlu5 (type-5 metabotropic glutamate) receptors improves recovery of sensorimotor function in rodent models of stroke, concomitant with restoration of functional connectivity in the sensorimotor cortex contralateral to the infarct. Here, we applied photopharmacology and light-activatable/deactivatable mGlu5 receptor negative allosteric modulators (NAMs) to localize when and where in the brain the recovery-enhancing effects occur from systemically administered mGlu5 receptor NAMs. METHODS: Stroke was induced in C57Bl/6 mice by permanent middle cerebral artery occlusion. Mice were treated with either JF-NP-26 (7-(Diethylamino)-2-oxo-2H‑chromen‑4‑yl)methyl (2‑((3‑fluorophenyl)ethynyl)‑4,6‑dimethylpyridin‑3‑yl)carbamate) or alloswitch-1. JF-NP-26 is a caged derivative of the mGlu5 receptor NAM, raseglurant, inactive on its own, and can be activated by visible light of 405 nm. Alloswitch-1 is an active mGlu5 receptor NAM that can be inactivated by light of 405 nm and subsequently reactivated by light of 520 nm. RESULTS: Permanent middle cerebral artery occlusion caused a sensorimotor deficit measured by 2 behavioral tests. Systemic administration of alloswitch-1 either 30 minutes or 48 hours after stroke enhanced recovery. This effect was rapidly abrogated when deactivating light was delivered to the contralateral somatosensory cortex and was subsequently restored by light-induced reactivation in the same region. No recovery-enhancing effects were observed when alloswitch-1 was activated or deactivated in the ipsilateral tissue. Specific light-induced activation of JF-NP-26 in the homotopic contralateral but not the ipsilateral somatosensory cortex enhanced functional recovery within 5 minutes after irradiation. None of the treatments changed infarct sizes. CONCLUSIONS: These findings demonstrate that the homotopic contralateral somatosensory cortex is a key site of action of systemic mGlu5 receptor NAMs in enhancing restorative processes important for recovery after stroke. Targeted, light-modulated drugs represent a potential future therapeutic strategy to enhance recovery of function after stroke.

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