The effect of diabetes mellitus on apoptosis in hippocampus: Cellular and molecular aspects

Abstract

Background:Diabetes mellitus is associated with cognitive deficits in humans and animals. These deficits are paralleled by neurophysiological and structural changes in brain. In diabetic animals, impairments of spatial learning, memory, and cognition occur in association with distinct changes in hippocampus, a key brain area for many forms of learning and memory and are particularly sensitive to changes in glucose homeostasis. However, the multifactorial pathogenesis of diabetic encephalopathy is not yet completely understood. Apoptosis plays a crucial role in diabetes-induce neuronal loss in hippocampus.Methods:The effects of diabetes on hippocampus and cognitive/behavioral dysfunctions in experimental models of diabetes are reviewed, with a focus on the negative impact on increased neuronal apoptosis and related cellular and molecular mechanisms.Results:Of all articles that were assessed, most of the experimental studies clearly showed that diabetes causes neuronal apoptosis in hippocampus through multiple mechanisms, including oxidative stress, inhibition of caspases, disturbance in expression of apoptosis regulator genes, as well as deficits in mitochondrial function. The balance between pro-apoptotic and anti-apoptotic signaling may determine the neuronal apoptotic outcome in vitro and in vivo models of experimental diabetes.Conclusions:Dissecting out the mechanisms responsible for diabetes-related changes in the hippocampal cell apoptosis helps improve treatment of impaired cognitive and memory functions in diabetic individuals.

Diabetes, adult neurogenesis and brain remodeling: New insights from rodent and zebrafish models

“…In contrast, T2D patients display more consistently moderate cognitive impairments in verbal memory tasks and complex information processing. 40,[118][119][120] An increasing number of data and epidemiological studies also link diabetes and Alzheimer disease; 121,122 T2D being associated with an almost 2-fold increased risk of dementia. 123,124 By modifying the BBB physiology, diabetes/hyperglycemia could disturb the microenvironment of neural stem cell niches and impairs neural stem cell activity and newborn cell survival.…”

“…37 STZ models of rat have shown that diabetes increases neuronal death through apoptotic mechanisms in the hippocampus. 40 For instance, the number of TUNEL-positive neurons was increased, [41][42][43] and the expression of pro-apoptotic protein such as Caspase-3 and Bax was upregulated. [44][45][46] Taken together, these data highlight that diabetes impairs neuronal survival by increasing Caspase-3 expression and activity, and apoptotic gene regulators 40 (Fig.…”

Influence of Chronic Coenzyme Q10 Supplementation on Cognitive Function, Learning, and Memory in Healthy and Diabetic Middle-Aged Rats

“…The following mechanisms are recognized for memory and cognitive deficits in DM: (1) hyperglycemia is considered the most important cause of diabetes complications as well as memory and cognitive impairments [11, 50]; (2) diabetes causes apoptosis and neuronal loss in the hippocampus and the frontal cortex, which are associated with cognitive impairment [14, 15, 51, 52]; (3) oxidative stress associated with cognitive dysfunction in diabetes increases neuronal damage and death through protein oxidation, DNA damage, and peroxidation of membrane lipids [13, 14, 51, 52]; (4) cholinergic (as one of the most important neurotransmitter systems involved in learning and memory formation mechanisms) dysfunction in the brain of diabetic rats via the increased activity of acetylcholinesterase (the enzyme responsible for degrading acetylcholine and terminating its physiological action) and decreasing levels of cholineacetyltransferase (the enzyme responsible for acetylcholine synthesis) contributes to DM memory impairment [16, 53]; (5) microvascular function change is another pathophysiological reason for cognitive impairment in diabetes, which is attenuated by some antioxidant agents [11]; and (6) changes in energy metabolism, cerebral blood flow, and the blood-brain barrier also cause memory and cognitive impairments [16, 54, 55]. As stated before, decreasing hyperglycemia in the diabetic groups with CoQ10 treatment may account for restoration of memory and cognitive function in DM.…”

Luteolin, a natural flavonoid, inhibits methylglyoxal induced apoptosis via the mTOR/4E-BP1 signaling pathway

“…Patients with long-standing diabetes commonly develop diabetic encephalopathy, which is characterized by cognitive decline 1 , neuronal apoptosis 2 , 3 , as well as neurochemical and structural abnormalities in the cortex and hippocampus 4 , 5 . Although the pathogenesis of diabetic encephalopathy is complex and not fully understood, methylglyoxal (MG) accumulation has been considered as one of the major contributing causes 6 , 7 .…”

“…The activated caspase-9, in turn, cleaves procaspase-3 to its active form, which induces cell apoptosis 18 . In the hippocampus of streptozotocin (STZ)-induced diabetic rats, Bax and caspase-3 mRNA or protein levels are considerably increased and related to impaired cognition as measured by the Morris water maze 3 . Therefore, neuronal apoptosis is likely to account for the concomitant emergence of cognitive impairments in the diabetic status.…”