Pilocarpine-induced Status Epilepticus (SE) induces functional and histological P- glycoprotein overexpression in cardiomyocytes, heart dysfunction and high ratio of sudden death in rats.

GELPI R; ROSSI A; CANELLAS C; LAZAROWSKI A; BUCHHOLZ B; MEN P; SALGUEIRO J; RAMOS AJ; MERELLI A; ZUBILLAGA M; AUZMENDI J

WASHINGTON DC

Congreso; AES Annual Meeting; 2017

RATIONALE:Refractory epilepsy (RE) has been associated with increased P-glycoprotein (P-gp) brain expression and highrisk of Sudden Unexpected Death in Epilepsy (SUDEP) by acute and fatal heart failure. Increased P-gpexpression in brain, liver and kidney of rats after SE induced by lithium-pilocarpine was also reported (Guo etal; 2009). We have previously described the association between fatal status epilepticus and asimultaneously progressive P-gp overexpression in brain and heart, after experimental repetitive seizuresinduced with pentylenetetrazole (Auzmendi et al. 2014). Heart failure with bradycardia or tachycardia wasalso described in patients and experimental models inducing RE. However, in-vivo images studies in theseconditions have not been investigated yet. 99mTc-SESTAMIBI radiotracer is a P-glycoprotein´s (P-gp)substrate, clinically used as biomarker of cardiologic SPECT studies in patients with heart failure. Wehypothesize that 99mTc-SESTAMIBI heart retention rate could show functional early heart damage in vivo,and to be a useful new biomarker tool as potential risk factor for fatal heart failure.METHODS:SE was induced on adult male Wistar rats (300 g; n=30) by lithium-pilocarpine administration. First lithiumchloride (127 mg/kg) was administrated ip and 20 h later animals received pilocarpine (30 mg/kg). In allanimals, 20 mg/kg of diazepam (i.p.) was used to stop seizures after 15 minutes of SE. Repeated SEepisodes, were induced sequentially once a week (four times, n= 20). Ten rats of this group were used for Pgpand HIF-1 detection in heart tissue section by immunohistochemistry. After 24h of each SE induction, tworats of this group were fixed by cardiac perfusion with 4% PFA in 0.1 M phosphate buffer. Other 10convulsive rats of this group, were anesthetized with ketamine (90-100 mg/Kg) plus xylazine hydrochloride(5-10mg/Kg), and administered with 99mTc-SESTAMIBI (37MBq i.v). In all cases, static images were acquiredwith animals being placed in a prone position, and analyzed by the ROI delineation that includes the wholeheart, and using a Gamma Camera for little animals and no less than 1.5x106 accounts by image wascollected. 99mTc-SESTAMIBI heart retention was sequentially evaluated in basal conditions (n=10), and 48hafter of each SE induction on remaining surviving rats. Spontaneous death rate was recorded. In remainingten convulsive rats SE was induced only one time, and heart rhythm and ECG registers were obtained incontrols and 24h after of SE. Additionally, cardiac chemical stress was developed by the administration ofdipyridamole (first dose: 0.56 mg/kg mg/kg; i.p., second doses 0.28 mg/kg). A non-convulsive control group(n=10) was treated with lithium plus saline and evaluated for all parameters studied.RESULTS:P-gp and HIF-1 overexpression in cardiomyocytes, a significant reduction in 99mTc-SESTAMIBI heart retentionas well as increased mortality were observed in SE-exposed animals as compared with the control group.When SE-exposed animals were stressed with dipyridamole, increased bradycardia or tachycardia as well asarrhythmias were also observed.