Triiodothyronine modulates neuronal plasticity mechanisms to enhance functional outcome after stroke.

Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE

Original Publication: London : BioMed Central, [2013]-

Brain/*drug effects ; Brain Ischemia/*physiopathology ; Neuronal Plasticity/*drug effects ; Neurons/*drug effects ; Neuroprotective Agents/*administration & dosage ; Stroke/*physiopathology ; Triiodothyronine/*administration & dosage; Animals ; Brain/physiopathology ; Brain Ischemia/metabolism ; Cells, Cultured ; Dendritic Spines/drug effects ; Dendritic Spines/physiology ; Homeostasis ; Humans ; Male ; Mice, Inbred C57BL ; Neurons/physiology ; Receptors, Thyroid Hormone/metabolism ; Recovery of Function/drug effects ; Stroke/metabolism ; Synaptotagmins/metabolism

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 (T 3 ) 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 T 3 actions.Our results show that T 3 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 T 3 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 T 3 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 T 3 actions. Summarizing, our data identify T 3 as a potential key therapeutic agent to enhance recovery of lost neurological functions after ischemic stroke.

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FO2019-0254; FO2018-0316 International Hjärnfonden; SFRH/BD/104679/2014 International Fundação para a Ciência e a Tecnologia; Technology UID / Multi / 00709/2019 International Fundação para a Ciência e a Tecnologia; Technology UID / Multi / 00709/2019 International Fundação para a Ciência e a Tecnologia; CENTRO-01-0145-FEDER-000013 International ICON 2020; CENTRO-01-0145-FEDER-000013 International ICON 2020; CENTRO-01-0145-FEDER-000013 International ICON 2020

Keywords: 3,5,3′,5′-tetraiodo-L-thyronine (T4); 3,5,3′-triiodo-L-thyronine (T3); Ischemia; Photothrombosis; Recovery; Stroke; Thyroid hormone receptors; Thyroid hormones

0 (Neuroprotective Agents)
0 (Receptors, Thyroid Hormone)
06LU7C9H1V (Triiodothyronine)
134193-27-4 (Synaptotagmins)

Date Created: 20191223 Date Completed: 20200911 Latest Revision: 20210110

20240829

PMC6925884

10.1186/s40478-019-0866-4

31864415