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- The role of transthyretin and thyroid hormones on functional recovery after experimental strokePublication . Talhada, Daniela de Fátima Rua Matos; Ruscher, Karsten; Santos, Cecília Reis Alves dos; Gonçalves, Isabel Maria Theriaga Mendes VarandaStroke remains one of the leading causes of death and disability worldwide. Focal ischemic cortical stroke results in tissue demise in the infarct core and neuronal dysfunction in areas surrounding the core. The loss of neuronal function triggers specific neuroanatomical and neurophysiological changes in both adjacent and remote areas during the first weeks after stroke onset. During this critical time window, there is a profound reorganization of cortical maps that is accompanied with spontaneous neuroplasticity, however, with limited and partially aberrant recovery of motor function. Induced plasticity with external interventions such as rehabilitation, facilitates recovery and promotes improvement of lost neurological function, albeit to a limited extent. Despite much effort has been spent in developing adjuvant therapies to foster spontaneous underlying endogenous mechanisms, none of the treatment attempts reached clinical use. Thus, rehabilitation remains the only evidence-based long-term treatment in stroke survivors. We hypothesized that by targeting thyroid hormones (TH) and their carrier protein transthyretin (TTR) might be a promising therapeutic strategy to foster endogenous mechanisms of neurorepair. TH are of fundamental importance for brain development and essential factors to warrant brain functions throughout life. In particular, the active form 3,5,3’-triiodo-L-thyronine (T3) is involved in the regulation of neuronal plasticity, stimulation of angiogenesis and neurogenesis as well as modulation of the dynamics of cytoskeletal elements and intracellular transport processes. These mechanisms overlap with those that have been identified to enhance recovery of lost neurological functions during the first weeks and months after ischemic stroke. Independent of its role as a TH carrier protein, TTR has been studied as a neuroprotective molecule in the brain, which has been emphasized as promising target to enhance lost neurological functions during the recovery phase after stroke. In the experimental setting, we investigated if TH and TTR are involved in the reorganization of cortical neuronal function after stroke. We found that administration of T3 50 μg/kg during the first two weeks after photothrombotic stroke in mice significantly enhanced functional recovery of lost neurological function without affecting infarct size. Motor improvement was accompanied by mechanisms of homeostatic regulation in the peri-infarct area in favor for an increased excitability. The mechanisms involved an increased level of the AMPA receptor subunit glutamate receptor 2 and synaptotagmin 1 and 2, which are pre-synaptic vesicles involved in neurotransmitter release. In addition, T3 increased dendritic spine density of principal neurons in the peri-infarct motor cortex. Moreover, we have shown that T3 regulates glutamatergic neurotransmission in cortical glutamatergic neurons. In parallel, T3 suppressed tonic GABAergic signaling in the peri-infarct tissue shown by a reduced number of parvalbumin positive neurons activity and decreased glutamic acid decarboxylase 65/67 levels. Despite TTR has been demonstrated as neuroprotective after ischemic stroke, we could not find ttr or TTR protein expression in the infarct core and peri-infarct area, and it seems unlikely that TTR is involved in mechanisms of tissue reorganization following PT during the recovery phase after stroke. Our results indicate that T3 modulates excitatory and inhibitory neurotransmission relevant for plasticity processes in the postischemic brain. T3 administration during the critical period for brain recovery regulates mechanisms that balance excitation – inhibition in favor of excitation. Further understanding and target those mechanisms might be exploited in future therapies to enhance functional recovery in stroke patients.
- Triiodothyronine modulates neuronal plasticity mechanisms to enhance functional outcome after strokePublication . Talhada, Daniela; Feiteiro, Joana; Costa, Ana Raquel; Talhada, Tiago; Cairrão, Elisa; Wieloch, Tadeusz; Englund, Elisabet; Santos, Cecilia Reis; Gonçalves, Isabel; Ruscher, KarstenThe 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.