Intracranial pancreatic islet transplantation attenuates cognitive dysfunctions in rat models of alzheimer’s disease induced by icv-streptozotozin (stz) administration, and in rat exposed to dizocilpine (mk-801)

Recent work has highlighted the important role of insulin action in the central nervous system on memory and mood. Intranasal insulin delivery was conducted in several clinical studies in Alzheimer's disease (AD) patients with modest efficacy. Our objectives were:1. To create an efficient and physiologically regulated insulin delivery to the brain by intracranial pancreatic islets transplantation. 2. To assess the capacity of the intracranially grafted islets to attenuate behavioral dysfunctions in rats exposed to the anti NMDA agent dizocilpine (MK-801), and in rat model of sporadic AD induced by icv-STZ administration. 3. To determine the effect of the grafted islets on brain insulin level and on peripheral metabolic parameters. Inbred adult Lewis rats were used. One group of rats were treated for 3 days with MK801 (0.15mg/kg ip) or vehicle. A second group was treated with a single icv-STZ (3 mg/kg) administration to create AD model. Half of the treated rats were transplanted with syngeneic pancreatic islets, which were grafted into the cranial subarachnoid cavity. Spatial memory was assessed 6 weeks post transplantation using the Morris Water Maze (MWM) test, and locomotion by the Open Field (OF) test. Metabolic effects were studied by analysis of brain insulin and peripheral glucose levels. Islets transplantation in rats significantly increased brain (frontal cortex and hippocampus) insulin levels without affecting blood glucose. In the OF test, rats with grafted islets were not different in motility parameters compared to intact controls. In the MWM paradigm, MK-801 treated rats and icv-STZ treated animal showed marked impaired spatial memory, and grafted islets significantly corrected it. Moreover, the icv-STZ treated rats presented a marked increase in body weight and this metabolic effect was reversed by the grafted islets.