CENTRAL ALLOXAN APPLICATION DOES NOT INFLUENCE LEARNIG AND MEMORY FUNCTIONS

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M Salkovic-Petrisic¹, Z Lacković¹, P Riederer²

¹ Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 11, HR 10 000 Zagreb, Croatia

² Department of Clinical Neurochemistry, Clinic for Psychiatry and Psychotherapy, University of Würzburg, Fuchslein str. 15, 97080Würzburg, Germany

INTRODUCTION: Alloxan is a betacytotoxic drug selectively toxic for insulin producing/secreting pancreatic beta cells which induces diabetes mellitus type I in rats following the parenteral administration of high doses. Its mechanism of action is related to glucose transporter GLUT2 membrane expression by which alloxan enters the beta cell, generates free radicals within the cell consequently damaging DNA and causing cell ATP depletion. Alloxan direct toxicity to GLUT2 mRNA has also been demonstrated. In line with the presence of insulin protein and its mRNA as well as the expression of GLUT2 in the brain intracerebroventricular (icv) administration of alloxan has been expected to induce some central effects. Indeed, alloxan-icv application was found to induce significant alterations of brain neurochemistry, particularly in monoaminergic transmission without altering steady-state blood glucose level. These brain monoamine alterations were reported to be in general similar following the icv application of another widely used betacytotoxic drug streptozotocin (STZ). Parenteral administration of STZ is used for induction of both diabetes type I and II and STZ-induced toxicity of both GLUT2 and insulin receptor have been found at the periphery. Central STZ administration does not induce symptoms of diabetes. Since STZ-icv rats have been found to demonstrate severe cognitive deficits in learning and memory functions and because of that were proposed as an experimental model of sporadic Alzheimer’s disease, we were investigated whether alloxan-icv treated rats also develop similar cognitive deficits.

MATERIAL AND METHODS: Alloxan (0.5 mg/kg) and streptozotocin (1 mg/kg) were administered to adult male Wistar rats under a general anaesthesia (chloralhydrate 300 mg/kg intraperitoneally) in a single icv dose. Learning and memory functions were tested in Morris Water Maze Swimming Test 3 months following the icv drug treatment. Data were analysed by Mann Whitney U test (p<0.05).

RESULTS: Three months following the alloxan-icv treatement no significant deficits in learning and memory functions were found in comparison to the respective controls measured as number of mistakes made while searching for the correct quadrant (median values 8 vs 9 for controls vs. alloxan-treated rats) and time spent in platform search (median values 57 vs. 55 sec for control and alloxan-treated rats).

CONCLUSION: Central administration of alloxan in a dose of 0.5 mg/kg is not associated with cognitive deficits in learning and memory functions three months after the drug-icv treatment suggesting differences between alloxan and streptozotocin in influencing the cognitive functions. It could be hypothesized that this ineffectiveness on cognition may be related to differences in the central mechanism of action of these two drugs, possibly at the level of brain insulin receptor signaling which has been found altered by STZ-icv administration but remains to be discovered following the alloxan-icv administration.