Systemic insulin-like growth factor-I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning/memory in normal adult rats.
Diabetic patients have impaired learning/memory, brain atrophy, and two-fold increased risk of dementia. The cause of cognitive disturbances that progress to dementia is unknown. Because neurotrophic insulin-like growth factor (IGF) levels are reduced in diabetic patients and rodents, and IGF can cross the blood-central nervous system barrier (B-CNS-B), the hypothesis was tested that IGF administered systemically can prevent cognitive disturbances, independently of hyperglycemia and a generalized catabolic state. Latency to escape to a hidden platform in the Morris Water Maze is used widely to test spatial memory, a hippocampus-dependent task. Adult rats were rendered diabetic with streptozotocin and implanted 4 weeks later with subcutaneous pumps that released either vehicle (D + Veh) or 20 microg/day IGF-I (D + IGF). Latency to escape to the hidden platform was prolonged in (D + Veh) versus non-diabetic rats (P < 0.003) 10.5 weeks after the onset of diabetes. Such prolongation was prevented in (D + IGF) versus (D + Veh) rats (P < 0.03). The data show that IGF-I can act across the B-CNS-B to prevent loss of cognition-related performance in the water maze independently of ongoing hyperglycemia and reduction in brain (P < 0.001) and whole body weight (P < 0.001) in diabetic rats. The hypothesis that brain IGF contributes to learning/memory was tested. An anti-IGF antibody, or preimmune serum, was infused into the lateral ventricles in non-diabetic rats. Learning in a passive avoidance task was impaired significantly in the IGF antibody versus preimmune serum-treated groups on test Days 1, 2, and 3 (P = 0.04, 0.02 and 0.004, respectively). The data together are consistent with a model in which brain IGF is essential for learning/memory, and a loss of IGF activity due to diabetes may contribute to cognitive disturbances.
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
Sean B
SB
Lupien
Erik J
EJ
Bluhm
Douglas N
DN
Ishii
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D012016:Reference Values; D013311:Streptozocin
D013311:Streptozocin; D007334:Insulin-Like Growth Factor I