Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) commonly co‐occur. T2DM increases the risk for AD by approximately twofold. Animal models provide one means of interrogating the relationship of T2DM to AD and investigating brain insulin resistance in the pathophysiology of AD. Animal models show that persistent hyperglycaemia results in chronic low‐grade inflammation that may contribute to the development of neuroinflammation and accelerate the pathobiology of AD. Epidemiological studies suggest that patients with T2DM who received treatment with specific anti‐diabetic agents have a decreased risk for the occurrence of AD and all‐cause dementia. Agents such as metformin ameliorate T2DM and may have other important systemic effects that lower the risk of AD. Glucagon‐like peptide 1 (GLP‐1) agonists have been associated with a decreased risk for AD in patients with T2DM. Both insulin and non‐insulin anti‐diabetic treatments have been evaluated for the treatment of AD in clinical trials. In most cases, patients included in the trials have clinical features of AD but do not have T2DM. Many of the trials were conducted prior to the use of diagnostic biomarkers for AD. Trials have had a wide range of durations and population sizes. Many of the agents used to treat T2DM do not cross the blood brain barrier, and the effects are posited to occur via lowering of peripheral hyperglycaemia and reduction of peripheral and central inflammation. Clinical trials of anti‐diabetic agents to treat AD are ongoing and will provide insight into the therapeutic utility of these agents.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/ejn.15619

Diabetes: Risk factor and translational therapeutic implications for Alzheimer's disease

Cannabidiol improves metabolic dysfunction in middle-aged diabetic rats submitted to a chronic cerebral hypoperfusion

Objectives Vascular dementia (VaD), being strongly associated with metabolic conditions is a major health concern around the world. Diabetes is a major risk factor for the development of VaD. This study investigates the efficacy of quercetin and folacin in diabetes induced vascular endothelium dysfunction and related dementia. Methods Single dose streptozotocin (STZ) (50 mg/kg i.p) was administered to albino Wistar rats (male, 200-250 g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), mitochondrial enzyme complex (I, II, and IV), inflammatory markers (interleukin-IL-6, IL-10, tumor necrosis factor-TNF-α, and myeloperoxidase-MPO), and acetylcholinesterase activity-AChE were also assessed. Quercetin (30 mg kg-1/60 mg kg-1) and folacin (30 mg kg-1/60 mg kg-1) were used as the treatment drugs. Donepezil (0.5 mg kg-1) was used as a positive control. Results STZ administered rats showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains' oxidative stress; inflammation; AChE activity, and decrease in mitochondrial complex (I, II, and IV) activity. Administration of quercetin and folacin in two different doses, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, and biochemical parameters. Conclusions STZ administration caused diabetes and VaD which was attenuated by the administration of quercetin and folacin. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced VaD conditions.

Behavioral and biochemical investigations to explore the efficacy of quercetin and folacin in experimental diabetes induced vascular endothelium dysfunction and associated dementia in rats.

Objective Vascular Dementia (VaD), is associated with metabolic conditions. Diabetes is a major risk factor for the development of VaD. This study investigates the efficacy of ulinastatin (UTI) and sulforaphane (SUL) in streptozotocin (STZ)-diabetes induced vascular endothelium dysfunction and related dementia. Methods Single dose STZ (50 mg/kg i.p.) was administered to Albino Wistar rats (male, 200-250 g). Morris water maze and attentional set shifting tests were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-α, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE, blood brain barrier (BBB) permeability and histopathological changes were also assessed. UTI (10,000 U/kg) and SUL (25 mg/kg) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5 mg/kg) was used as a positive control. Results STZ-administered rats showed reduction in body weight, learning, memory, reversal learning, executive functioning, impairment in endothelial function, BBB permeability, increase in serum glucose, brains' oxidative stress, inflammation, AChE-activity, BBB permeability and histopathological changes. Administration of UTI and SUL alone as well as in combination, significantly and dose dependently attenuated the STZ-diabetes-induced impairments in the behavioral, endothelial, and biochemical parameters. Conclusion STZ administration caused diabetes and VaD which was attenuated by the administration of UTI and SUL. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced VaD.

Efficacy of Ulinastatin and Sulforaphane Alone or in Combination in Rat Model of Streptozotocin Diabetes Induced Vascular Dementia

Diabetes is among the most prevalent diseases of the modern world and is strongly linked to an increased risk of numerous neurodegenerative disorders, although the exact pathophysiological mechanisms are not clear yet. Insulin resistance is a serious pathological condition, connecting type 2 diabetes, metabolic syndrome, and obesity. Recently, insulin resistance has been proven to be connected also to cognitive decline and dementias, including the most prevalent form, Alzheimer’s disease. The relationship between diabetes and Alzheimer’s disease regarding pathophysiology is so significant that it has been proposed that some presentations of the condition could be termed type 3 diabetes.

/pdf/a-pathophysiological-intersection-of-diabetes-and-alzheimers-gmw1lalr.pdf

A Pathophysiological Intersection of Diabetes and Alzheimer’s Disease

Intermittent streptozotocin administration induces behavioral and pathological features relevant to Alzheimer's disease and vascular dementia.

ANIMALS Fourty-four male Sprague-Dawley rats (~8 weeks old) were used throughout the studies. The animals were single-housed in a standard animal facility with a 12–12 hr light–dark cycle, with food and water available ad libitum. All procedures were performed during the light phase and in accordance with the University of Nevada, Las Vegas Animal Care and Use Committee and NIH guidelines for ethical treatment of research subjects.

/pdf/an-acute-inflammatory-response-in-a-diabetic-alzheimer-s-51p7etn3wt.pdf

An Acute Inflammatory Response in a Diabetic Alzheimer’s Disease Model

Major theories of addiction propose that stress plays an important role in the motivation to abuse substances. Research suggests that the likelihood of an individual to abuse a substance is higher for someone with previous exposure to a stressful event than one without that prior experience (Reed et al., 2007). 5-α reduced neurosteroids are endogenous regulators of stress and anxiety and may play an important role in stress-induced sensitization, such as drug abuse perpetuated by previous or current stressful events (Bortolato et al., 2011). Allopregnanolone (AP) is a neurosteroid and a potent modulator of the GABAA receptors. In the present study, we examined the role of AP by using the 5-α reductase antagonist, finasteride. On days 1-2, 30 male Long-Evans rats were pretreated with vehicle, 10 mg/kg, or 25 mg/kg of finasteride. On day 3, rats received either control treatment or restraint stress. On day 4, all rats were tested for behavioral responses to saline and 1.0 mg/kg of d-amphetamine. Hippocampal tissue was extracted on day 5. Hippocampal AP levels and plasma corticosterone were quantified using an enzyme-linked immunosorbent assay (ELISA). Two-way ANOVA confirmed significance of stress on amphetamine-induced stereotypies but not of finasteride dose. Unfortunately, this study did not demonstrate a relationship between neurosteroids, stress, and amphetamine responses as we hypothesized. More research will need to be performed to observe to what extent neurosteroids could be involved in addiction. INTRODUCTION The chronic, recurring nature of addiction remains a widespread problem in the United States. Even after successful treatment and long-term abstinence, individuals may still relapse several months or years later. Animal and human studies also suggest long term and acute stressors increase sensitivity to cocaine and amphetamine (Sinha et al., 2006, Robinson and Becker, 1986). 5-α reduced neurosteroids may play an important role in stressinduced sensitization as endogenous regulators of stress and anxiety (Bortolato et al., 2011). Therefore, the goal of this study was to determine what role 5α-reduced neurosteroids might play in the development of stress-induced sensitization to amphetamines. This study is primarily based on another study performed by L.M Pritchard in 2005 titled SexSummer 2015 UNLV McNair Journal

McNair Research Journal - Summer 2015

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Intermittent streptozotocin administration induces behavioral and pathological features relevant to Alzheimer's disease and vascular dementia.

An Acute Inflammatory Response in a Diabetic Alzheimer’s Disease Model

McNair Research Journal - Summer 2015