|Year : 2016 | Volume
| Issue : 1 | Page : 57
The effect of diabetes mellitus on apoptosis in hippocampus: Cellular and molecular aspects
Akram Sadeghi1, Javad Hami2, Shahnaz Razavi1, Ebrahim Esfandiary1, Zahra Hejazi3
1 Department of Anatomical Sciences and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Anatomical Sciences, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
3 Department of Genetic Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Submission||12-May-2015|
|Date of Acceptance||17-Oct-2015|
|Date of Web Publication||10-Mar-2016|
Department of Anatomical Sciences and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan 81744 176
Source of Support: None, Conflict of Interest: None
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.
Keywords: Apoptosis, central nervous system complication, diabetes mellitus, hippocampus
|How to cite this article:|
Sadeghi A, Hami J, Razavi S, Esfandiary E, Hejazi Z. The effect of diabetes mellitus on apoptosis in hippocampus: Cellular and molecular aspects. Int J Prev Med 2016;7:57
|How to cite this URL:|
Sadeghi A, Hami J, Razavi S, Esfandiary E, Hejazi Z. The effect of diabetes mellitus on apoptosis in hippocampus: Cellular and molecular aspects. Int J Prev Med [serial online] 2016 [cited 2017 Mar 27];7:57. Available from: http://www.ijpvmjournal.net/text.asp?2016/7/1/57/178531
| Introduction|| |
Diabetes mellitus is the most common serious metabolic disorder in humans and is clinically defined as a group of metabolic diseases characterized by hyperglycemia as a result of defects in insulin secretion or resistance to insulin action or both. , There are multiple types of diabetes, but the most common forms are type 1 and type 2 diabetes. Type 1 diabetes (previously defined as insulin-dependent diabetes mellitus) is characterized by an autoimmune-mediated destruction of pancreatic β-cells, leading to insulin deficiency. Consequently, patients require insulin treatment for survival and withdrawal from insulin treatment leads to ketoacidosis. Type 2 diabetes (previously defined as noninsulin-dependent diabetes mellitus) is characterized by insulin resistance and relative (rather than absolute) insulin deficiency. Treatments aim to reduce insulin resistance (for example, with diet, exercise or drug therapy) and to increase endogenous insulin secretion. Eventually, exogenous insulin can be needed. ,,, The epidemiology of diabetes mellitus in developed countries has been assessed using screening methods to detect undiagnosed cases. The incidence of type 1 diabetes is 8-20 per 100,000 patient-years in children up to 18 years of age. After the age of 20 years, the incidence is lower with little further effect of age.  The incidence of type 2 diabetes is estimated to be about 5 per 100,000 patient-years in subjects up to 29 years of age, increasing sharply up to 500 per 100,000 patient-years in subjects over 70 years.  The prevalence of diabetes ranges from about 2% in subjects aged 20-44 years to 18% in subjects aged 65-74 years, and over 20% in subjects aged 85 years and older. , Impaired glucose tolerance can be present in 7-10% of the subjects of 50 years and older.  Because the average age of the western population is increasing, and the incidence of type 2 diabetes is particularly high among the elderly, the overall prevalence of diabetes will increase significantly in the next few decades. ,,
| Methods|| |
The keywords "diabetes," "Apoptosis," and "hippocampus" were searched in PubMed, MEDLINE, and EMBASE databases with the following limits: English language and published in the last 15 years (2001-2015). Article titles and abstracts were screened, and potentially relevant articles were retrieved and evaluated. This review included published studies that examined the effect of diabetes on hippocampal apoptosis [Table 1], and it summarizes and synthesizes the highlights of the selected articles. The known cellular and molecular mechanisms involved in hippocampus neuronal apoptosis (i.e., gene regulators, caspases activity, and oxidative stress) are also discussed. Most of the reviewed behavioral studies involved the evaluation of hippocampal apoptosis in a model of experimental diabetes.
|Table 1: Effects of experimental diabetes models on hippocampal apoptosis |
Click here to view
| Results|| |
The evidence of the impact of metabolic diseases such as diabetes mellitus on central nervous system (CNS) considerably grew up in the last decade. ,,,, Neuroradiological and neurophysiological studies provide further evidence that both types of diabetes are associated with functional and structural disturbances in the brain. ,,,, The development of these complications is dependent on the duration of diabetes and the quality of metabolic control, and can only be partially prevented by intensive insulin treatment. , These disturbances are related to acute hypoglycemia or severe hyperglycemia and stroke and are referred to as diabetic encephalopathy, a term that encompasses functional impairment of cognition, cerebral signal conduction, neurotransmission and synaptic plasticity, and underlying structural pathology associated with diabetes. , Evidence from several line of studies clearly indicated that individuals with type 1 or type 2 diabetes have been shown to have poorer performance in a wide range of neuropsychological tests. , Type 1 diabetic patients might have impairments in learning and memory, problem-solving, and mental and motor speed. The deficits are generally modest, but can occasionally be severe. ,,
The results of neuropsychological studies of type 2 diabetic patients are also more consistent. , Moderate cognitive impairment is reported, particularly in tasks involving verbal memory or complex information processing. Basic attentional processes, motor reaction time, and short-term memory are relatively unaffected.  Moreover, recent epidemiological studies demonstrate an association between diabetes and vascular dementia as well as Alzheimer's disease. ,,,,,
Over recent decades, studies have also provided evidence indicating the deleterious effects of type 1 diabetes mellitus on structure of the brain. , Duration-related or chronic effects of type 1 diabetes mellitus on the brain are manifested at all levels of CNS from microscopic to macroscopic level. , Macroscopically neuroimaging studies have demonstrated a high incidence of abnormalities such as temporal lobe sclerosis, declines in white matter volume in parahippocampal gyrus, temporal and frontal lobes as well as decreased gray matter volumes and densities of the thalami, hippocampi, insular cortex, superior and middle temporal, and frontal gyri. ,
In experimental models of type 1 diabetes mellitus, a vast spectrum of neuronal changes has been reported. These pathological abnormalities include synaptic and neuronal alterations, degeneration, increased cerebral microvasular permeability, and neuronal loss which collectively can lead to cognitive impairment and higher risk of development dementia. ,,
In summary, diabetes is associated with an "encephalopathy" characterized by slowly progressive, clinically prominent cognitive impairments accompanied by brain neurophysiological and structural disorders. A better understanding of the underlying mechanisms may allow us to challenge the concept that the accelerated cognitive decline in these individuals is an irrevocable process.
Cognitive deficits in diabetic rodents
Behavioral studies in diabetic rodents have produced very different results, because of differences in the animal models used and in the duration of diabetes. ,, An important factor appears to be the nature of the stimulus used in the behavioral paradigm. ,
The performance of streptozotocin (STZ)-diabetic mice is clearly impaired in relatively simple tasks such as active avoidance in a shuttle box or T-maze.  The cognitive performance of STZ-diabetic rats has also been tested in the Morris water maze. ,,,, Spatial learning in this task involves multiple cognitive components such as problem-solving, enhanced selective attention, formation of internal representations of the external world, and storage and retrieval of relevant information. ,,,,
Young-adult STZ-diabetic rats begin to display learning deficits in the Morris maze ten weeks after the induction of diabetes. ,, In the spatial version of the task, it is indicated that diabetic rats have a poorer comprehension of the task than do controls. While in aged rats (24 months), the diabetic deficit in water-maze performance was larger than expected from the effect in young-adult rats, which suggests that there is an interaction between aging and diabetic cerebral dysfunction. 
Effects of diabetes on hippocampus
Numerous studies have shown that experimental diabetes has negative impacts and induce apoptosis in hippocampal neurons via multiple known mechanisms [Table 2]. Hippocampus is one of the most sensitive regions of the brain to the metabolic disorders including diabetes mellitus. , The hippocampus is a horseshoe-shaped paired structure, with one hippocampus located in the left brain hemisphere and the other in the right hemisphere. , It is a crucial part of the limbic system, which plays a pivotal role in memory formation, emotional, adaptive, and reproductive behaviors , and also is particularly important in forming new memories and connecting emotions and senses, such as smell and sound, to memories. , The hippocampus acts as a memory indicator by sending memories out to the appropriate part of the cerebral hemisphere for long-term storage and retrieving them when necessary. ,,
|Table 2: Effects of experimental diabetes models and measurement methods of hippocampal apoptosis |
Click here to view
The hippocampus itself is divided into two interlocking sectors, the dentate gyrus and the hippocampus proper (cornu ammonis). The dentate gyrus has three layers such as (1) the granular layer containing the densely packed cell bodies of the granule-cells, (2) the molecular layer formed by the intertwining apical dendrites of the granule-cells and their afferents, and (3) the polymorph layer in the hilus of the dentate gyrus containing the initial segments of the granule-cell axons as they gather to form the glutamergic mossy fiber bundle. , Hippocampus proper as an archeocortical structure has been divided into several layers as follows: (1) The alveus; containing the axons of the pyramidal cells, (2) the stratum oriens, a layer between the alveus and the pyramidal cell bodies which contains the basal dendrites of the pyramidal cells, (3) the stratum pyramidal, (4) the stratum radiatum, and (5) the stratum lacunosum/molecular, which are the proximal and distal segments of the apical dendritic tree, respectively. In the CA3 field, an additional layer is recognized in the stratum lucidum, interposed between the pyramidal cell bodies and the stratum radiatum, receiving the mossy-fibers input from the dentate granule-cells. Each CA3 giant pyramidal neuron with large dendritic spines receive as many as 10-50 mossy fibers from dentate gyrus, and send their axons into the fimbria. New memory formation and consolidation process of events by hippocampus depend on the integrity of hippocampus internal circuits. ,
Hippocampus structural complexity has made it vulnerable to the many pathological conditions such as diabetes mellitus. ,, Studies have shown that cell proliferation continues in granular layer of dentate gyrus constantly. This unique neuronal renew is necessary for memory formation. ,, Any factor disturbing the balance between neuronal proliferations/death may result in memory and learning impairment. , Studies have demonstrated that experimental diabetes causes decreased granular cells proliferation and neuronal death (necrosis/apoptosis) in CA3 and dentate gyrus regions. ,,, In this line, Li et al., reported hippocampal neuronal death in a spontaneous rat model of type 1 diabetes mellitus, accompanied by some functional cognitive alterations after a long period of diabetes (8 months). 
Although neuronal death has been considered the main leading cause of diabetic CNS and peripheral neuropathies, the mode of neuronal death in type 1 diabetes mellitus has remained as a matter of controversy. ,,
| Discussion|| |
Effects of diabetes on neuronal apoptosis
Apoptosis, a morphologically distinct form of programmed cell death, is an active, tightly regulated, metabolic, and genetically encoded form of cell death, in which any harm done to the organism by this process is minimized. ,, It may occur during normal physiological conditions, for example, during embryonic development, where unnecessary cells may die by apoptosis and deregulation of apoptosis may cause pathological conditions such as neurodegenerative diseases. ,,
This suicidal pathway is characterized by several morphological and biochemical aspects such as the mitochondrial depolarization and alterations in phospholipid asymmetry, membrane blebbing, the condensation of the nucleus and cytoplasm, and the activation of an endonucleolytic process which degrades nuclear deoxyribonucleic acid (DNA). ,
The decision to undergo apoptosis may be determined by the balance between pro-apoptotic and anti-apoptotic signaling events triggered by environmental (extracellular) factors, such as tumor necrosis factor-α, Fas ligand (FasL/CD95L), transforming growth factor-β, and cytokines. Most growth factors and cytokines promote cell survival, growth, and differentiation by triggering anti-apoptotic signaling on their target cells. ,,
In the previous work, Jakobsen et al. showed a significant loss of neocortical neurons in STZ-induced diabetic rats.  Neuronal apoptosis also occurs in the hypothalamic nuclei in the diabetic Chinese hamster.  The nature of neuronal apoptosis was not defined in these early studies or it was determined as to whether neuronal loss was associated with cognitive impairments.
Preclinical literature consistently reports that the hippocampal environment of diabetic animals favors apoptosis, as evidenced by significant elevations in apoptotic markers [Table 1] and [Table 2]. In the type 1 diabetic rat, neuronal counts of hippocampal pyramidal cells were performed in the hippocampal sub-regions (CA1-CA4) and found no significant differences at 2 months of diabetes. Nevertheless, there was 37% and 24% loss of pyramidal cells in the CA1 and CA2 regions, respectively, in 8 months diabetic animals, and no significant decreases were reported in neuronal densities of other hippocampal sub-regions.  These data suggest a duration-related effects of diabetes on neuronal density decline in hippocampus. There are also several in vitro and in vivo studies indicating that hippocampal neuronal loss occurs in diabetic animals and this may be a major contributing mechanism to memory and learning impairments. , There is some evidence demonstrating no apoptosis in hippocampal pyramidal neurons or any cognitive deficits in 8 weeks diabetic rats.  On the other hand, in 8 months diabetic rats, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeled positive neurons, positive DNA laddering, increased Bax expression, and caspase 3 activity were evident and related to decreased neuronal density and impaired Morris water maze performances [Table 1] and [Table 2]. ,,,,,, Therefore, duration-related apoptosis is likely to account for the neuronal loss and the concomitant emergence of cognitive impairments in the diabetic animals.
Diabetes and caspases activity
Many of the morphological changes associated with apoptosis are orchestrated by activation of a cascade of proteases termed caspases. The caspases are a family of cysteine proteases comprising at least 14 members. Activation of caspases represents a point of irreversibility in the cell death process. The regulation of caspases occurs by two distinct molecular signaling pathways, depending on whether the cell signals activating apoptosis originate extracellularly, thereby activating the extrinsic pathway or intracellularly, , thereby activating the intrinsic pathway. ,, There is evidence demonstrating that the diabetes experimental model had hippocampal apoptosis resulting from caspase-dependent mechanisms [Table 2]. ,,,,,,, Jafari Anarkooli et al. found a significant increase in activity of caspases-3, the most important member of caspases family in hippocampus of STZ-induced diabetic rats after 8 weeks. 
Diabetes and apoptotic gene regulators
A large number of genes and proteins have been implicated in the control of apoptosis. These can be categorized by their activities at discrete steps in the apoptotic pathway as well as their relationships with specific disease states. A diverse assortment of triggers activates the cascade, which is subject to tight homeostatic regulation by a number of regulators or modulators of the death pathway. The "point of no return" in apoptosis is reached when caspases become enzymatically active in cleaving target proteins (the "executioners" of apoptosis). The Bcl-2 family of factors regulates caspase activation either negatively (e.g. Bcl-2 itself) or positively (e.g. Bax). Other apoptosis modulators reside further upstream and are thought to activate cascades, which are in turn subject to regulation by downstream factors such as Bcl-2. ,,
A variety of factors has also been demonstrated to antagonize apoptotic pathways, both during physiological events (such as normal development) and in pathological states. Heavily studied anti-apoptotic genes in mammalian cells are Bcl-2 and Bcl-XL. Bcl-2 was first identified as part of a common translocation in human follicular lymphoma. , This gene displayed the unusual property of extending cell survival rather than promoting cell proliferation per se. Bcl-2 is capable of dimerizing with a number of related factors that comprise a family of apoptotic regulators. Although their mechanisms of action are not well-understood, some Bcl-2 family members actually promote apoptosis while others (like Bcl-2 itself) promote antagonize apoptosis. ,,
The members of the Bcl-2 family of proteins are important components of the intrinsic apoptotic pathway, regulating mitochondrial outer membrane permeabilization and the release of pro-apoptotic factors, such as cytochrome C, from mitochondria. , In addition, Bcl-2 family members are key regulators of apoptosis because they connect the extrinsic and intrinsic pathways. Bcl-2 was shown to promote tumorigenesis by inhibiting apoptosis, instead of promoting cell proliferation. ,,,
Members of the Bcl-2 family of proteins are important regulators that facilitate or prevent the release of cytochrome C from mitochondria into the cytoplasm. ,, Bcl-X is a member of the Bcl-2 family. The Bcl-X gene closely resembles Bcl-2 and functions to regulate cell death. This gene acts to inhibit apoptosis similarly to Bcl-2 and antagonizes apoptosis in a variety of tissues. ,, Bax is another pro-apoptotic member of the Bcl-2 family. This and other pro-apoptotic Bcl-2 family members may counteract their ability to protect cell death. ,,
The results of a study by Jafari Anarkooli et al. showed that after 8 weeks of diabetes-induction using STZ (60 mg/kg) as diabetogenic agent, Bax expression was considerably increased in hippocampus of STZ-induced diabetic rats at both mRNA and protein levels, while the expression of Bcl-2 and Bcl-xL was significantly reduced at both mRNA and protein levels. They also reported that the Bax/Bcl-2 and Bax/Bcl-xL ratios (as the main index of apoptotic cell death) were significantly increased; signifying hyperglycemia-induced apoptosis in hippocampus of STZ-induced diabetic rats could be mediated by the mitochondrial pathway [Table 2]. ,,,,,,
Diabetes and oxidative stress
Increasing evidence in both clinical and experimental studies suggests that oxidative stress plays a pivotal role in the pathogenesis of both types of diabetes mellitus [Table 2]. ,,,,,,, High glucose level can stimulate free radical production via glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. On the other hand, weak defense system of the body becomes unable to counteract the enhanced reactive oxygen species (ROS) generation and as a result condition of imbalance between ROS and their protection occurs which leads to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. ,,, Furthermore, STZ-treated rats that received supplement with antioxidant properties such as fish oil, Vitamin E, and a grape seed extract also had a significant decrease in the number of neurons with apoptotic markers [Table 1] and [Table 2]. ,,
Recent studies have demonstrated free radicals and ROS as the main driving causes of neuronal apoptosis in diabetic paradigm. ,, Investigations have suggested that ROS and the resulting oxidative stress play a pivotal role in apoptosis. ROS are constantly generated under normal conditions as a consequence of aerobic metabolism. , ROS include free radicals such as the superoxide anion (O2−), hydroxyl radicals, and the nonradical hydrogen peroxide (H 2 O 2 ). They are particularly transient species due to their high chemical reactivity and can react with DNA, proteins, carbohydrates, and lipids in a destructive manner. , The cell is endowed with an extensive antioxidant defense system to combat ROS, either directly by interception or indirectly through reversal of oxidative damage. When ROS overcome the defense systems of the cell and redox homeostasis is altered, the result is oxidative stress. ,,
Increasing evidence provides supporting that oxidative stress and apoptosis are closely linked physiological phenomena and are implicated in pathophysiology of some of the chronic diseases including diabetes mellitus, AIDS, amyotrophic lateral sclerosis, retinal degenerative disorders, cancer, Alzheimer's and Parkinson's, and ischemia of heart and brain. ,,
Oxidative stress is implicated in the pathogenesis of several diseases including diabetes. ,, Evidently, the brain is particularly vulnerable. This is not surprising as the CNS is highly aerobic and thus extremely susceptible to oxidative stress. In addition, the antioxidant defense of the brain is relatively low having almost no catalase and very low levels of glutathione. ,,
Bcl-2 protein has also been shown to prevent cells from apoptosis apparently by an antioxidative mechanism. Taken together ROS, and the resulting cellular redox change, can be part of signal transduction pathway during apoptosis. ,,
It is now established that mitochondria play a prominent role in the regulation of apoptosis. During mitochondrial dysfunction, several essential players of apoptosis, including pro-caspases, cytochrome C, Smac/DIABLO, apoptosis-inducing factor, and apoptotic protease-activating factor-1 (APAF-1), are released into the cytosol following the formation of a pore in the mitochondrial membrane called the "Permeability transition pore." These pores are thought to form through the action of the pro-apoptotic members of the Bcl-2 family of proteins, which in turn are activated by apoptotic signals such as cell stress, free radical damage, or growth factor deprivation. The multimeric complex formation of cytochrome C, APAF-1, and caspase 9 activates downstream caspases leading to apoptotic cell death. All the three functional phases of apoptosis are under the influence of regulatory controls. Mitochondria also play an important role in amplifying the apoptotic signaling from the death receptors, with receptor recruited caspase 8 activating the pro-apoptotic Bcl-2 protein. ,,,,
| Conclusions|| |
It is now well-established that diabetes mellitus is associated with impaired cognitive function in human and animals. Animal models of both type 1 and 2 diabetes mellitus have confirmed the detrimental effect of chronic high blood glucose levels on learning and memory. Experimentally, learning and memory deficits in STZ-diabetic rats have been associated with neuronal loss, apoptosis induction in neurons of hippocampus. In addition, recent studies revealed the dark neuron production in hippocampus of diabetic rats. Apoptosis is an active, tightly regulated, metabolic, and genetically encoded form of cell death, in which any harm done to the organism by this process is minimized. It may occur during normal physiological or pathological conditions such as diabetes mellitus. Apoptosis is well-regulated by several internal and external regulators such as expression of a number of (pro-apoptotic and anti-apoptotic) genes.
Dissecting out the mechanisms responsible for the induction of apoptosis in hippocampal neurons that partially reflects the effects of diabetes on learning and memory impairments observed in diabetic human and animals helps to improve the therapy. The development of diabetes complications is directly dependent on the duration of the disease and the quality of metabolic control. Until now, it can only be partially prevented by intensive insulin treatment.
Financial support and sponsorship
This research was supported by Isfahan University of Medical Sciences (Grant No. 393026).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Cosson E. Diagnostic criteria for gestational diabetes mellitus. Diabetes Metab 2010;36(6 Pt 2):538-48.
Khan MN, Khan FA, Sultana S, Dilawar M, Ijaz A, Khan MJ, et al
. Impact of new diagnostic criteria of diabetes mellitus. J Coll Physicians Surg Pak 2007;17:327-30.
Dagogo-Jack S, Santiago JV. Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions. Arch Intern Med 1997;157:1802-17.
Yi SS. Effects of exercise on brain functions in diabetic animal models. World J Diabetes 2015;6:583-97.
Tran L, Zielinski A, Roach AH, Jende JA, Householder AM, Cole EE, et al
. Pharmacologic treatment of type 2 diabetes: Oral medications. Ann Pharmacother 2015;49:540-56.
Conde Barreiro S, Rodríguez Rigual M, Bueno Lozano G, López Siguero JP, González Pelegrín B, Rodrigo Val MP, et al
. Epidemiology of type 1 diabetes mellitus in children in Spain. An Pediatr (Barc) 2014;81:189.e1-12.
Huber CA, Schwenkglenks M, Rapold R, Reich O. Epidemiology and costs of diabetes mellitus in Switzerland: An analysis of health care claims data, 2006 and 2011. BMC Endocr Disord 2014;14:44.
Harris MI. Epidemiology of diabetes mellitus among the elderly in the United States. Clin Geriatr Med 1990;6:703-19.
Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 yr. Diabetes 1987;36:523-34.
Cukierman-Yaffe T. Diabetes, dysglycemia and cognitive dysfunction. Diabetes Metab Res Rev 2014;30:341-5.
McCrimmon RJ, Ryan CM, Frier BM. Diabetes and cognitive dysfunction. Lancet 2012;379:2291-9.
Reijmer YD, van den Berg E, Ruis C, Kappelle LJ, Biessels GJ. Cognitive dysfunction in patients with type 2 diabetes. Diabetes Metab Res Rev 2010;26:507-19.
Alvarez EO, Beauquis J, Revsin Y, Banzan AM, Roig P, De Nicola AF, et al
. Cognitive dysfunction and hippocampal changes in experimental type 1 diabetes. Behav Brain Res 2009;198:224-30.
Kodl CT, Seaquist ER. Cognitive dysfunction and diabetes mellitus. Endocr Rev 2008;29:494-511.
Matanovic D, Popovic S, Parapid B, Dubljanin E, Stanisavljevic D, Ille T. Evaluation of neurophysiological parameters and good metabolic control in patients with type 1 diabetes mellitus. Srp Arh Celok Lek 2012;140:285-9.
Zhou X, Zhang J, Chen Y, Ma T, Wang Y, Wang J, et al
. Aggravated cognitive and brain functional impairment in mild cognitive impairment patients with type 2 diabetes: A resting-state functional MRI study. J Alzheimers Dis 2014;41:925-35.
van Harten B, Oosterman JM, Potter van Loon BJ, Scheltens P, Weinstein HC. Brain lesions on MRI in elderly patients with type 2 diabetes mellitus. Eur Neurol 2007;57:70-4.
Meece J. Diabetes mellitus: Pathophysiology and complications. Int J Pharm Compd 2003;7:17-20.
Mooradian AD. Pathophysiology of central nervous system complications in diabetes mellitus. Clin Neurosci 1997;4:322-6.
Pirart J. Diabetes mellitus and its degenerative complications: A prospective study of 4,400 patients observed between 1947 and 1973 (3 rd
and last part) (author's transl). Diabete Metab 1977;3:245-56.
Gispen WH, Biessels GJ. Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 2000;23:542-9.
Chuiko MR, Bodykhov MK, Skvortsova VI. Characteristics and peculiarities of the course of encephalopathy in diabetes mellitus. Zh Nevrol Psikhiatr Im S S Korsakova 2010;110(5 Pt 1):4-8.
Brands AM, Henselmans JM, de Haan EH, Biessels GJ. Diabetic encephalopathy: An underexposed complication of diabetes mellitus. Ned Tijdschr Geneeskd 2003;147:11-4.
Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP. The effects of type 1 diabetes on cognitive performance: A meta-analysis. Diabetes Care 2005;28:726-35.
Strachan MW, Deary IJ, Ewing FM, Frier BM. Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care 1997;20:438-45.
Ma L, Wang J, Li Y. Insulin resistance and cognitive dysfunction. Clin Chim Acta 2015;444:18-23.
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group, Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary P, et al
. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007;356:1842-52.
Bryan RN, Bilello M, Davatzikos C, Lazar RM, Murray A, Horowitz K, et al
. Effect of diabetes on brain structure: The action to control cardiovascular risk in diabetes MR imaging baseline data. Radiology 2014;272:210-6.
Ferguson SC, Blane A, Perros P, McCrimmon RJ, Best JJ, Wardlaw J, et al
. Cognitive ability and brain structure in type 1 diabetes: Relation to microangiopathy and preceding severe hypoglycemia. Diabetes 2003;52:149-56.
Musen G, Lyoo IK, Sparks CR, Weinger K, Hwang J, Ryan CM, et al
. Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry. Diabetes 2006;55:326-33.
Sima AA, Kamiya H, Li ZG. Insulin, C-peptide, hyperglycemia, and central nervous system complications in diabetes. Eur J Pharmacol 2004;490:187-97.
Huber JD, VanGilder RL, Houser KA. Streptozotocin-induced diabetes progressively increases blood-brain barrier permeability in specific brain regions in rats. Am J Physiol Heart Circ Physiol 2006;291:H2660-8.
Sridhar GR, Lakshmi G, Nagamani G. Emerging links between type 2 diabetes and Alzheimer's disease. World J Diabetes 2015;6:744-51.
Yonguc GN, Dodurga Y, Adiguzel E, Gundogdu G, Kucukatay V, Ozbal S, et al
. Grape seed extract has superior beneficial effects than Vitamin E on oxidative stress and apoptosis in the hippocampus of streptozotocin induced diabetic rats. Gene 2015;555:119-26.
Ghasemi R, Zarifkar A, Rastegar K, Maghsoudi N, Moosavi M. Insulin protects against Aß-induced spatial memory impairment, hippocampal apoptosis and MAPKs signaling disruption. Neuropharmacology 2014;85:113-20.
Sun LJ, Hou XH, Xue SH, Yan F, Dai YJ, Zhao CH, et al
. Fish oil modulates glycogen synthase kinase-3 signaling pathway in diabetes-induced hippocampal neurons apoptosis. Brain Res 2014;1574:37-49.
Jafari Anarkooli I, Barzegar Ganji H, Pourheidar M. The protective effects of insulin and natural honey against hippocampal cell death in streptozotocin-induced diabetic rats. J Diabetes Res 2014;2014:491571.
Alipour M, Salehi I, Ghadiri Soufi F. Effect of exercise on diabetes-induced oxidative stress in the rat hippocampus. Iran Red Crescent Med J 2012;14:222-8.
Zhao CH, Liu HQ, Cao R, Ji AL, Zhang L, Wang F, et al
. Effects of dietary fish oil on learning function and apoptosis of hippocampal pyramidal neurons in streptozotocin-diabetic rats. Brain Res 2012;1457:33-43.
Chen Z, He Y, Song C, Dong Z, Su Z, Xue J. Sericin can reduce hippocampal neuronal apoptosis by activating the Akt signal transduction pathway in a rat model of diabetes mellitus. Neural Regen Res 2012;7:197-201.
Chen Y, Li L, Li Z, Huang X, Zhang L, Chen W. Effects of naokang erhao decoction on cognitive ability and hippocampal apoptosis-related proteins in diabetic rats. Zhongguo Zhong Yao Za Zhi 2011;36:1519-23.
Zhang T, Jia W, Sun X. 3-n-butylphthalide (NBP) reduces apoptosis and enhances vascular endothelial growth factor (VEGF) up-regulation in diabetic rats. Neurol Res 2010;32:390-6.
Jafari Anarkooli I, Sankian M, Ahmadpour S, Varasteh AR, Haghir H. Evaluation of Bcl-2 family gene expression and caspase-3 activity in hippocampus STZ-induced diabetic rats. Exp Diabetes Res 2008;2008:638467.
Kuhad A, Bishnoi M, Tiwari V, Chopra K. Suppression of NF-kappabeta signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacol Biochem Behav 2009;92:251-9.
Cosar M, Songur A, Sahin O, Uz E, Yilmaz R, Yagmurca M, et al
. The neuroprotective effect of fish n-3 fatty acids in the hippocampus of diabetic rats. Nutr Neurosci 2008;11:161-6.
Sima AA, Li ZG. The effect of C-peptide on cognitive dysfunction and hippocampal apoptosis in type 1 diabetic rats. Diabetes 2005;54:1497-505.
Li ZG, Zhang W, Sima AA. C-peptide prevents hippocampal apoptosis in type 1 diabetes. Int J Exp Diabetes Res 2002;3:241-5.
Biessels GJ, Kamal A, Ramakers GM, Urban IJ, Spruijt BM, Erkelens DW, et al
. Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes 1996;45:1259-66.
Popoviç M, Biessels GJ, Isaacson RL, Gispen WH. Learning and memory in streptozotocin-induced diabetic rats in a novel spatial/object discrimination task. Behav Brain Res 2001;122:201-7.
Flood JF, Mooradian AD, Morley JE. Characteristics of learning and memory in streptozocin-induced diabetic mice. Diabetes 1990;39:1391-8.
Chen L, Gong S, Shan LD, Xu WP, Zhang YJ, Guo SY, et al
. Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats. Neurosci Bull 2006;22:1-6.
Kamal A, Biessels GJ, Duis SE, Gispen WH. Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: Interaction of diabetes and ageing. Diabetologia 2000;43:500-6.
Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: Effects of insulin treatment. Brain Res 1998;800:125-35.
Pamidi N, Satheesha Nayak BN. Effect of streptozotocin induced diabetes on rat hippocampus. Bratisl Lek Listy 2012;113:583-8.
Foghi K, Ahmadpour S. Diabetes mellitus type1 and neuronal degeneration in ventral and dorsal hippocampus. Iran J Pathol 2014;9:33.
Witter M, Amaral DG. The Rat Nervous System. California, USA: Elsevier Academic; 2004.
Squire LR. Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychol Rev 1992;99:195-231.
Lewis S. Learning and memory: Hippocampus plays multiple choice. Nat Rev Neurosci 2012;13:600.
Turgut YB, Turgut M. A mysterious term hippocampus involved in learning and memory. Childs Nerv Syst 2011;27:2023-5.
Jarrard LE. On the role of the hippocampus in learning and memory in the rat. Behav Neural Biol 1993;60:9-26.
Kang JO, Kim SK, Hong SE, Lee TH, Kim CJ. Low dose radiation overcomes diabetes-induced suppression of hippocampal neuronal cell proliferation in rats. J Korean Med Sci 2006;21:500-5.
Kitamura T, Inokuchi K. Role of adult neurogenesis in hippocampal-cortical memory consolidation. Mol Brain 2014;7:13.
Koehl M, Abrous DN. A new chapter in the field of memory: Adult hippocampal neurogenesis. Eur J Neurosci 2011;33:1101-14.
Kitabatake Y, Sailor KA, Ming GL, Song H. Adult neurogenesis and hippocampal memory function: New cells, more plasticity, new memories? Neurosurg Clin N Am 2007;18:105-13, x.
Van der Borght K, Havekes R, Bos T, Eggen BJ, Van der Zee EA. Exercise improves memory acquisition and retrieval in the Y-maze task: Relationship with hippocampal neurogenesis. Behav Neurosci 2007;121:324-34.
Kobilo T, Yuan C, van Praag H. Endurance factors improve hippocampal neurogenesis and spatial memory in mice. Learn Mem 2011;18:103-7.
Choi JH, Hwang IK, Yi SS, Yoo KS, Lee CH, Shin HC, et al
. Effects of streptozotocin-induced type 1 diabetes on cell proliferation and neuronal differentiation in the dentate gyrus; correlation with memory impairment. Korean J Anat 2009;42:41-8.
Zhang WJ, Tan YF, Yue JT, Vranic M, Wojtowicz JM. Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurol Scand 2008;117:205-10.
Li ZG, Zhang W, Grunberger G, Sima AA. Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 2002;946:221-31.
Ahmadpour S, Sadeghi Y, Sheibanifar M, Haghir H. Neuronal death in dentate gyrus and ca3 in diabetic rats: Effects of insulin and ascorbic acid. Hormozan J Med Sci 2010;13:13-6.
Winkler G, Kempler P. Pathomechanism of diabetic neuropathy: Background of the pathogenesis-oriented therapy. Orv Hetil 2010;151:971-81.
Vinik AI. Diabetic neuropathy: Pathogenesis and therapy. Am J Med 1999;107:17S-26S.
Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol 2007;35:495-516.
Umanskii SP. Apoptosis: Molecular and cellular mechanisms. Mol Biol (Mosk) 1996;30:487-502.
Hung RW, Chow AW. Apoptosis: Molecular mechanisms, regulation and role in pathogenesis. Can J Infect Dis 1997;8:103-9.
Topuridze ML, Kipiani VA, Pavliashvili NS, Kipiani NV, Petriashvili TG. Molecular mechanisms of apoptosis. Georgian Med News 2007;150:38-45.
Radi E, Formichi P, Battisti C, Federico A. Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimers Dis 2014;42 Suppl 3:S125-52.
Conradt B. Genetic control of programmed cell death during animal development. Annu Rev Genet 2009;43:493-523.
Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell 2011;147:742-58.
Yuan J, Horvitz HR. A first insight into the molecular mechanisms of apoptosis. Cell 2004;116 2 Suppl:S53-6.
Jakobsen J, Sidenius P, Gundersen HJ, Osterby R. Quantitative changes of cerebral neocortical structure in insulin-treated long-term streptozocin-induced diabetes in rats. Diabetes 1987;36:597-601.
Garris DR, Diani AR, Smith C, Gerritsen GC. Depopulation of the ventromedial hypothalamic nucleus in the diabetic Chinese hamster. Acta Neuropathol 1982;56:63-6.
Verhagen AM, Vaux DL. Molecular mechanisms of apoptosis: An overview. Results Probl Cell Differ 1999;23:11-24.
Schwartzman RA, Cidlowski JA. Apoptosis: The biochemistry and molecular biology of programmed cell death. Endocr Rev 1993;14:133-51.
Kukhta VK, Marozkina NV, Sokolchik IG, Bogaturova EV. Molecular mechanisms of apoptosis. Ukr Biokhim Zh (1999) 2003;75:5-9.
Oyenihi AB, Ayeleso AO, Mukwevho E, Masola B. Antioxidant strategies in the management of diabetic neuropathy. Biomed Res Int 2015;2015:515042.
Karunakaran U, Park KG. A systematic review of oxidative stress and safety of antioxidants in diabetes: Focus on islets and their defense. Diabetes Metab J 2013;37:106-12.
Maritim AC, Sanders RA, Watkins JB 3 rd
. Diabetes, oxidative stress, and antioxidants: A review. J Biochem Mol Toxicol 2003;17:24-38.
Johansen JS, Harris AK, Rychly DJ, Ergul A. Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical practice. Cardiovasc Diabetol 2005;4:5.
Sonoda N, Inoguchi T. Role of oxidative stress in pathogenesis of diabetic complications. Nihon Rinsho 2012;70 Suppl 5:231-5.
Matough FA, Budin SB, Hamid ZA, Alwahaibi N, Mohamed J. The role of oxidative stress and antioxidants in diabetic complications. Sultan Qaboos Univ Med J 2012;12:5-18.
Van Dam PS, Van Asbeck BS, Erkelens DW, Marx JJ, Gispen WH, Bravenboer B. The role of oxidative stress in neuropathy and other diabetic complications. Diabetes Metab Rev 1995;11:181-92.
Niedowicz DM, Daleke DL. The role of oxidative stress in diabetic complications. Cell Biochem Biophys 2005;43:289-330.
de Oliveira DM, Ferreira Lima RM, El-Bachá RS. Brain rust: Recent discoveries on the role of oxidative stress in neurodegenerative diseases. Nutr Neurosci 2012;15:94-102.
Shibata N, Kobayashi M. The role for oxidative stress in neurodegenerative diseases. Brain Nerve 2008;60:157-70.
Potashkin JA, Meredith GE. The role of oxidative stress in the dysregulation of gene expression and protein metabolism in neurodegenerative disease. Antioxid Redox Signal 2006;8:144-51.
[Table 1], [Table 2]
|This article has been cited by|
||Diabetes, adult neurogenesis and brain remodeling: New insights from rodent and zebrafish models
| ||Anne-Claire Dorsemans,David Couret,Anaļs Hoarau,Olivier Meilhac,Christian Lefebvre dęHellencourt,Nicolas Diotel |
| ||Neurogenesis. 2017; : 00 |
|[Pubmed] | [DOI]|
||Expression of apoptosis-regulatory genes in the hippocampus of rat neonates born to mothers with diabetes
| ||Hossein Haghir,Javad Hami,Nassim Lotfi,Mostafa Peyvandi,Simagol Ghasemi,Mehran Hosseini |
| ||Metabolic Brain Disease. 2017; |
|[Pubmed] | [DOI]|
||Brain injury with diabetes mellitus: evidence, mechanisms and treatment implications
| ||Sherifa A. Hamed |
| ||Expert Review of Clinical Pharmacology. 2017; : 1 |
|[Pubmed] | [DOI]|