Systemic insulin‐like growth factor‐I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning/memory in normal adult rats

Abstract

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.

Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects

“…These observations agree with previous suggestions of a role of IGF-I on cognition in rodents 11,13,14 and provide a mechanistic frame to help understand parallel changes in serum IGF-I levels and cognitive status in humans. [3][4][5][6][7][8] If these observations are translated to the human situation, we would anticipate that both in aged humans and in GH/IGF-Ideficient subjects, the number of hippocampal GABAergic and glutamatergic synapses may be imbalanced as compared to young and healthy individuals, which in turn may relate to cognitive disturbances known to occur in both cases.…”

“…9,10 A more direct relationship between IGF-I and cognition is derived from animal experiments showing that administration of IGF-I restores cognition in aging animals, 11,12 that inhibition of IGF-I action results in cognitive impairment in adult rodents, 13,14 or that old mice with serum IGF-I deficiency show cognitive impairment. 15 Based on all this evidence, we recently proposed that serum IGF-I contributes to building a 'cognitive reserve', 16 a concept that refers to the availability of functional resources supporting cognition which was originally coined to explain relative resilience to dementia in relation to education level.…”

Impact of Energy Intake and Expenditure on Neuronal Plasticity

“…A causal relationship for running-induced alterations in serum IGF-1 and hippocampal neurogenesis was proposed, based on experiments using peripheral blockade of IGF-1 . Administration of exogenous IGF-1 ameliorates cognitive deficits in diabetic animals, and enhances hippocampal learning in non-diabetic animals (Lupien et al 2003). Additionally, the effects of running on hippocampal BDNF levels are prevented when peripheral upregulation of IGF-1 is blocked (Chen and Russo-Neustadt 2007).…”

Hormonal Signaling Systems of the Brain in Diabetes Mellitus

“…As a result, the brain DNA loss in DM1 is prevented (Serbedzija et al, 2009). The administration of IGF-1 to STZ rats prevents irrespective of the severity of hyperglycemia IGF-1 reduction in the brain and the DMassociated cognitive disturbances (Lupien et al, 2003). Anti-IGF-1 antibody infused into the lateral ventricles led, on the contrary, to deterioration of learning and memory functions of diabetic as well as non-diabetic rats.…”