DIMETHYLTRIPTAMINE ATTENUATES SPREADING DEPOLARIZATION IN THE ISCHEMIC RAT BRAIN
Írisz Szabó1,Viktória Éva Varga1, Tímea Körmöczi2, 3, Szabolcs Dvorácskó4, Dóra Hantosi1, Ákos Menyhárt1, Ferenc Bari1, Róbert Berkecz2, 3, Csaba Tömböly4, Botond Penke3, Eszter Farkas1
Endogenous dimethyltriptamine (DMT) exerts tissue protective effects in case of stress. Among others, DMT activates the Sigma1-receptor (Sig1-R), an intracellular chaperon/receptor located in the endoplasmic reticulum membrane to control intracellular Ca2+ levels. Previously, exogenous DMT was shown to achieve anti-inflammatory and anti-hypoxic effects through Sig1-Rs in vitro. Our aim was to test the neuroprotective effect of DMT administered to rats exposed to cerebral ischemia/hypoxia, and to confirm the implication of Sig1-Rs. Global forebrain ischemia/reperfusion was induced in isoflurane-anesthetized, adult, male Sprague-Dawley rats (n=20) by the bilateral occlusion and later release of the common carotid arteries. Hypoxia was induced before reperfusion with the withdrawal of oxygen from the anesthetic gas mixture. Two open craniotomies on the right parietal bone served the continuous elicitation of spreading depolarization (SD) with 1M KCl (caudal), and the acquisition of local field potential and cerebral blood flow (rostral). The femoral vein was cannulated for the infusion of DMT, PRE-084 (selective Sig1-R agonist, 1mg/bwkg/h) or their vehicle. Both DMT and PRE‑084 suppressed SD, as evidenced either by the reduced amplitude of SD (-16.5±4.1 vs -20.1±1.3 mV, DMT vs vehicle) or the smaller area under the curve of SDs (697.8±378.8 vs 1179.9±305.8 mV*s, PRE-084 vs vehicle). Neither of the agents altered the hyperemic response coupled to SD (18.7±10.6 vs 22.7±13.2 vs 25.1±10.9 pp; DMT vs PRE-084 vs vehicle). In summary, DMT emerges as a promising agent to inhibit the evolution of injurious SDs in cerebral ischemia through the activation of Sig1-R.