Changes in Thyroid Hormone Receptors After Permanent Cerebral Ischemia in Male Rats

Thyroid hormones (TH) and receptors (TRs) may play an important role in the pathophysiology of acute cerebral ischemia. In the present study, we sought to determine whether serum triodothyronine (T3)/thyroxine (T4) and brain TRs (TR alpha 1, TR beta 1) might change after experimental stroke. Male adult Wistar rats were subjected to permanent middle cerebral artery occlusion (group P) and compared to sham-operated controls (group S). Animals were followed clinically for 14 days until brain collection for Western blot (WB) or neuropathological analysis of TRs in three different brain areas (infarcted tissue, E1; noninfarcted ipsilateral hemisphere, E2; and contralateral hemisphere, E3). Analysis of serum TH levels showed a reduction of T4 in group P (p = 0.002) at days 2 to 14, while half of the animals also displayed low T3 values (p = 0.012) on day 14. This T4 reduction was inversely correlated to the clinical severity of stroke and the concomitant body weight loss (p < 0.005). WB analysis of TR alpha 1 and TR beta 1 protein expression showed heterogenic responses at day 14: total and nuclear TR alpha 1 were similar between the two groups, while total TR beta 1 decreased 7.5-fold within E1 (p a parts per thousand currency signaEuro parts per thousand 0.001) with a concomitant 1.8-fold increase of nuclear TR beta 1 in E2 area (p = 0.03); TR beta 1 expression did not differ in E3. Neuropathological analysis revealed that activated macrophages/microglia exclusively expressed nuclear TR alpha 1 within the infarct core. Astrocytes mildly expressed nuclear TR alpha 1 in and around the infarct, along with a prominent TR beta nuclear signal restricted in the astrocytic scar. Neurons around the infarct expressed mainly TR alpha 1 and, to a milder degree, TR beta. Surprisingly enough, we detected for the first time a TR beta expression in the paranodal region of Ranvier nodes, of unknown significance so far. Our data support that cerebral ischemia induces a low TH response, associated with significant and heterogenic changes in brain TR expression. These findings could imply an important role of TH signaling in cerebral ischemia.