Abstract

The development of new therapeutic approaches for stroke patients requires a detailed understanding of the mechanisms that enhance recovery of lost neurological functions. The efficacy to enhance homeostatic mechanisms during the first weeks after stroke will influence functional outcome. Thyroid hormones (TH) are essential regulators of neuronal plasticity, however, their role in recovery related mechanisms of neuronal plasticity after stroke remains unknown. This study addresses important findings of 3,5,3′-triiodo-L-thyronine (T3) in the regulation of homeostatic mechanisms that adjust excitability – inhibition ratio in the post-ischemic brain. This is valid during the first 2 weeks after experimental stroke induced by photothrombosis (PT) and in cultured neurons subjected to an in vitro model of acute cerebral ischemia. In the human post-stroke brain, we assessed the expression pattern of TH receptors (TR) protein levels, important for mediating T3 actions.Our results show that T3 modulates several plasticity mechanisms that may operate on different temporal and spatial scales as compensatory mechanisms to assure appropriate synaptic neurotransmission. We have shown in vivo that long-term administration of T3 after PT significantly (1) enhances lost sensorimotor function; (2) increases levels of synaptotagmin 1&2 and levels of the post-synaptic GluR2 subunit in AMPA receptors in the peri-infarct area; (3) increases dendritic spine density in the peri-infarct and contralateral region and (4) decreases tonic GABAergic signaling in the peri-infarct area by a reduced number of parvalbumin+ / c-fos+ neurons and glutamic acid decarboxylase 65/67 levels. In addition, we have shown that T3 modulates in vitro neuron membrane properties with the balance of inward glutamate ligand-gated channels currents and decreases synaptotagmin levels in conditions of deprived oxygen and glucose. Interestingly, we found increased levels of TRβ1 in the infarct core of post-mortem human stroke patients, which mediate T3 actions. Summarizing, our data identify T3 as a potential key therapeutic agent to enhance recovery of lost neurological functions after ischemic stroke.

Highlights

  • Loss of motor function following ischemic stroke is the most enduring and disabling consequence [4, 26]

  • Summarizing, we demonstrate that (1) T3 enhanced recovery of lost motor function in an experimental model of stroke, (2) T3 increased levels of synaptotagmin 1&2 and levels of post-synaptic glutamate receptor 2 (GluR2) subunit in alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors in the periinfarct area, (3) T3 increased dendritic spine density in the ipsilateral and contralateral regions and (4) T3 decreased tonic GABAergic signaling in the peri-infarct area by a reduced number of parvalbumin-positive (PV+) / c-fos+ neurons and glutamic acid decarboxylase 65/67 (GAD 65/67) protein levels

  • Treatment with T3 improves functional recovery after PT without affecting infarct size We first assessed if treatment with T3 or T4 at 5 or 50 μg/kg enhances motor function in mice subjected to unilateral PT

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Summary

Introduction

Loss of motor function following ischemic stroke is the most enduring and disabling consequence [4, 26]. Despite the attempt to find neuroprotective treatments that mitigate tissue damage and loss of motor function, their translation into clinical practice has been disappointing. Thrombectomy and thrombolysis in the acute phase after stroke are the only effective treatments to restore blood flow and minimize brain damage. Beyond the acute phase constant and consistent specific rehabilitation programs are instrumental to partially regain brain function, dependent on size and brain regions affected by stroke [37]. The options to minimize the damage after ischemic stroke remains sub-optimal and there is need for new therapeutic approaches that target restorative processes

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