A host of diabetes-related insults to the central nervous PLA2G4F/Z system (CNS) have been clearly documented in type-1 and -2 diabetic patients as well as experimental animal models. CNS disorders. Changes in plasma glucose levels (hyper- or hypoglycemia) have been associated with altered BBB transport functions (e.g. glucose insulin choline amino acids etc.) integrity (tight junction disruption) and oxidative stress in the CNS microcapillaries. Last two implicating a potential causal role for upregulation and activation of the receptor for advanced glycation end products (RAGE). This type I membrane-protein also transports amyloid-beta (Aβ) from the blood into the brain across the BBB thus establishing a link between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD also referred to as “type 3 diabetes”). Hyperglycemia has been associated with progression of cerebral ischemia and the consequent enhancement of secondary brain injury. Difficulty in detecting vascular impairments in the large heterogeneous brain microvascular bed and dissecting out the impact of hyper- and hypoglycemia has led to controversial results especially with regard to the effects of diabetes on BBB. In this article we review the major findings and current knowledge with regard to the impact of diabetes on BBB integrity and function as well as specific brain microvascular effects of hyper- and hypoglycemia. and including DM patients). The pathophysiology of microvascular complications in diabetes encompasses major biochemical pathways while the common endpoint appears to be mitochondrial superoxide overproduction in the endothelial cells lining the vascular walls of the blood vessels. The increased superoxide production causes the activation of four major pathways involved in the pathogenesis of complications: increase in polyol and hexosamine pathways flux activation of Protein Kinase C (PKC) and increased formation CCT239065 of advanced glycation end product (AGE) ligands originating from proteins lipids and nucleic acids (e.g. LDL) [2 3 RAGE activation initiates a vicious cycle eliciting more oxidative stress generation [3 4 and subsequently evoking vascular inflammation [5] and thrombosis [6] thereby implicating a potential vascular damage [7 8 Furthermore the overproduction of reactive oxygen species (ROS) inactivates endothelial nitric oxide synthase (eNOS) and prostacyclin synthase thereby impairing the vascular tone [2 9 10 A growing body of evidence from recent clinical and experimental CCT239065 studies suggests that prolonged hyperglycemic conditions particularly in type 2 DM elicit a progressive impairment of neuronal function in the brain [10]. Stroke and cerebral ischemia are typical CNS complications related to diabetes due to the impairments in cerebral vascular supply [11]. Diabetic patients are also at higher risk of experiencing stroke than normal CCT239065 population [11-13] and 50% of stroke-affected individuals have been diagnosed with hyperglycemia [14]. It is also reported that subjects with type 2 DM have significantly lower brain volume and are more likely to have single or multiple cerebral infarcts compared to normoglycemic individuals [13]. In addition preclinical studies in mice suggest that vascular injury occurring in response to an ischemic insult following stroke is significantly exacerbated in diabetic subjects [15] and the situation is further worsened by recurrent hypoglycemia [16]. Type 2 diabetes can negatively impact the outcome of stroke (ischemic brain damage); in fact increases the risk of stroke as demonstrated in type 2 diabetic mice [15]. Conversely hyperglycemia is also associated with high levels of mortality and morbidity during cerebral ischemia perhaps caused by increased cerebral hematoma expansion [14] and higher risk of cerebral hemorrhage due to tissue Plasminogen Activator (tPA) activation and superoxide production damaging the BBB [17] Recent studies also evoke a role for the AGE-RAGE system activated by hyperglycemia leading to a further enhancement of oxidative stress and amplification of inflammatory signals from nearby leukocytes [18 19 Improved glycemic control in these patients seem CCT239065 to ameliorate these pathological conditions [10] however rapid normalization of plasma glucose levels in hyperglycemic subjects can lead to cerebral hypoglycemia thus favoring cognitive decline [20-25]. Other studies have demonstrated an association between altered glycemic conditions and.