The effects of intra-dorsal hippocampus infusion of pregnenolone sulfate on memory function and hippocampal BDNF mRNA expression of biliary cirrhosis-induced memory impairment in rats.
Learning and memory impairment is one of the most challenging complications of cirrhosis and present treatments are unsatisfactory. The exact mechanism of cirrhosis cognitive dysfunction is unknown. Pregnenolone sulfate (PREGS) is an excitatory neurosteroid that acts as a N-methyl-D-aspartate (NMDA) receptor agonist and GABAA receptor antagonist. In this study we evaluated the effect of intra CA1 infusion of PREGS on cirrhotic rats' memory function using the Y-maze test. Hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression was also evaluated. Three weeks after bile duct ligation (BDL) surgery, rats were under stereotaxic surgery for insertion of two guide cannulas in the CA1 region of the hippocampus. After 1-week of recovery, PREGS was administered through CA1 cannulas in cirrhotic rats, while control or sham groups received vehicle. For evaluation of NMDA receptor role in memory-enhancing effects of PREGS, DL-2-Amino-5-phosphonopentanoic acid (AP5) which is a potent and competitive antagonist of NMDA receptor, co-administered with PREGS and for assessment of hippocampal BDNF mRNA expression, quantitative Real-time reverse transcriptase-PCR (RT-PCR) was used. Results showed that 28 days after BDL, cirrhotic animals' memory significantly decreased in comparison with control and sham groups, while PREGS infusion could restore memory impairment (P<0.05). PREGS effects on memory of cirrhotic rats were antagonized by DAP5. RT-PCR findings have shown that hippocampal relative BDNF mRNA expression was up-regulated in PREGS-treated groups in comparison with the BDL group (P<0.001). Our findings suggest that PREGS has a memory-enhancing effect in cirrhosis memory deficit in acute therapy and this effect may be through NMDA (glutamate) receptor involvement and BDNF mRNA expression.
Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Dastgheib
Experimental research center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Dehpour
Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran.
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Heidari
Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Nanomedicine and Nanobiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: moezile@yahoo.com.
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Moezi
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage; D008105:Liver Cirrhosis, Biliary / Q000150:complications*; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D011284:Pregnenolone / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors
D019208:Brain-Derived Neurotrophic Factor; D058787:GABA-A Receptor Antagonists; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C018370:pregnenolone sulfate; D011284:Pregnenolone; D015763:2-Amino-5-phosphonovalerate
NMDA receptor; brain-derived neurotrophic factor; learning and memory; liver cirrhosis; pregnenolone sulfate