Abstract
T2 (3,5-diiodo-I-thyronine) is an active metabolite of T3 (3,3’,5’-triiodothyronine), a key hormone secreted by the thyroid gland. It has been found to significantly increase mitochondrial respiration and cytochrome oxidizes activity in both in vitro and in vivo studies. T2 has a much more rapid stimulation of metabolic rate (1 hour for T2 vs 24 hours for T3). Neuroprotective effects of T3 have previously been demonstrated. Here, we have investigated the neuroprotective effects of T2 on brain ischemia and edema formation in t-MCAO mice model of brain stroke. CD-1 mice (25-30 g) were treated with T2 (5 mg/kg) or vehicle control (PBS) by i.v. injection through the jugular vein 30 min before brain stroke was induced. To confirm appropriate placement of the monofilament suture, cortical blood perfusion values were monitored by Laser-Doppler flowmetry during surgical preparation and for 30 min after cerebral ischemia. After 1h of t-MCAO monofilament suture was withdrawn for blood reperfusion and animals were sacrificed after 24h. 1 mm coronal brain slices were prepared and stained with 1% TTC (2,3,5-triphenyltetrazolium chloride) for t-MCAO. Volumes of brain ischemia and edema formation were evaluated. In vivo results for t-MCAO (1h) showed that T2 (5 mg/kg) reduced brain infarct volume by 42% (p<0.005), and edema formation by 65% (p<0.001). Preliminary gene expression studies showed that T2 has marked influence on gene programs involved in neuronal energy metabolism, mitochondrial biogenesis, ROS generation and brain edema. Ongoing work in our lab is elucidating the exact mechanisms of neuroprotective actions of T2. Neuroprotective effects of T2 in t-MCAO brain stroke model suggest that T2 is a potential new candidate for developing of neuroprotective therapies for brain ischemia and edema. Our studies showed that T2, even though mechanistically distinct from T3, retains the neuroprotective activity of T3 in ischemic stroke and raises the possibility that T2 activity has a role in the neuroprotection seen by T3.
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