Kunjan R. Dave

Hypoglycemia is a frequent and often serious complication of diabetes management. While its acute effects on cognition are well documented, growing evidence suggests that recurrent or severe hypoglycemia exposure may also contribute to long-term cognitive decline and increased risk of dementia in patients with diabetes. In fact, clinical and epidemiological data suggest that repeated hypoglycemic events are associated with lower performance in multiple cognitive domains, especially in pediatric and elderly populations. Moreover, meta-analyses and cohort studies highlight a significant association between severe hypoglycemia and increased risk of dementia while cognitive impairment has been shown to also increase the risk of hypoglycemia. This suggests a potential bidirectional relationship between hypoglycemia and cognitive decline. On the molecular level, both animal and human studies reveal that recurrent hypoglycemia induces oxidative stress, impairs mitochondrial dynamics, and leads to synaptic injury, particularly in vulnerable brain regions such as the hippocampus and cortex. These findings underscore the need for personalized glucose management strategies that minimize hypoglycemia risk while maintaining glycemic targets, particularly in populations vulnerable to cognitive impairment. This review summarizes the current understanding of the impact of hypoglycemia on brain function, including its structural, cellular, metabolic, and cognitive consequences.

BACKGROUND: Significant cognitive impairment follows cardiac arrest, yet few interventions restore memory. We previously demonstrated that physical exercise (PE) after asphyxial cardiac arrest (ACA) mitigates memory deficits and cell loss in the septal nuclei, but not in the hippocampus in rats. Given the critical role of the septum in modulating hippocampal theta oscillations, essential for memory, we hypothesize that PE preserves memory by safeguarding septal pacemaker neurons and septo-hippocampal theta activity. METHODS: Adult male and female rats underwent 8 minutes of ACA or sham surgery and were randomly assigned to 5 days of treadmill running PE or sedentary conditions. Long- and short-term memory were assessed using fear conditioning and Y-maze tests. Immunohistochemistry quantified septal cholinergic and gamma-aminobutyric acid–ergic neurons. Local field potential recordings evaluated oscillatory activity across the septo-hippocampal network. RESULTS: ACA induced persistent deficits in memory and disrupted theta oscillations throughout the septum and cornu ammonis 1 (CA1) laminae. These changes were accompanied by selective loss of cholinergic and gamma-aminobutyric acid–ergic septal neurons. PE markedly improved cognitive performance and restored theta power across the septo-hippocampal axis. Only cholinergic, not gamma-aminobutyric acid–ergic, neurons were preserved after PE. All effects were consistent across sexes. Importantly, enhancements in CA1 theta power closely tracked behavioral recovery, implying that reestablishment of cholinergic-driven network dynamics plays a central role in memory restoration. CONCLUSIONS: This study is the first to directly implicate PE-induced cholinergic neuron preservation in the reengagement of septo-hippocampal circuitry and cognitive recovery post cardiac arrest. Rather than relying on hippocampal cell survival, the observed memory improvements appear to stem from reinstated interregional theta synchrony. These findings define a novel mechanistic pathway for promoting functional recovery via targeted circuit-level rehabilitation after ischemic brain injury.

Antidiabetic treatment is linked with an increased risk of hypoglycemia. Several clinical studies have demonstrated that hypoglycemia exposure elevates the

Aims: Diabetes is a widespread disease associated with long‐term complications. Treatment of diabetes alleviates these complications but cause an increased risk of recurrent hypoglycemia (RH). Hypoglycemia exposure increases the risk of cardiovascular events by an unknown mechanism. Since the effect of mild/moderate hypoglycemia on thrombosis is unknown, we studied the effect of RH exposure on platelet function and thrombosis in insulin‐treated diabetic (ITD) rats. Materials and Methods: ITD rats were randomized to either control or hypoglycemia groups. First, we determined the minimum duration and frequency of RH exposure that increases the risk of thrombosis and the time window after a single hypoglycemic episode (SH)/RH exposure with increased risk of thrombosis in male ITD rats. Next, we confirmed whether RH exposure increases the risk of thrombosis in female ITD rats. Subsequently, we evaluated the impact of RH exposure on platelet susceptibility to aggregation and platelet gene expression. Results: One hour hypoglycemia increased the clot weight and the effect of SH and RH on thrombosis lasted for at least 1 and 7 days post‐exposure, respectively. A minimum frequency of twice‐a‐week hypoglycemia exposure for 6 weeks increased the risk of thrombosis in male ITD rats. Increased susceptibility of platelet activation was observed in RH‐exposed male ITD rats. Lastly, we identified RH‐induced alterations in the platelet transcriptome in male ITD rats. We also confirmed that RH exposure increases the risk of thrombosis in female rats. Conclusions: Understanding the mechanism of RH‐induced platelet activation and thrombosis may help limit thrombotic complications in diabetes.

Background: Current therapies to treat excessive bleeding are associated with significant complications, which may outweigh their benefits. Red blood cell-derived microparticles (RMPs) are a promising hemostatic agent. Previous studies demonstrated that they reduce bleeding in animal models, correct coagulation defects in patient blood, and have an excellent safety profile. However, their exact mechanism of action is not known. We investigated the potential role of RMPs on primary and secondary hemostasis. Methods: To evaluate the effects of RMPs, prepared using high-pressure extrusion, on primary hemostasis, we employed platelet aggregometry with platelet inhibitors, eptifibatide, and ticagrelor, with and without RMPs. To evaluate their effects on secondary hemostasis, we employed thromboelastography with plasma deficient in factors VII, VIII, IX, XI, and XII with and without RMPs. Results: We found that RMPs significantly increased collagen-induced platelet aggregation. However, there were no significant differences with and without RMP in the presence of the platelet inhibitors, indicating that RMPs may work through these receptors, either directly or indirectly. For secondary hemostasis, RMPs significantly decreased clotting times for plasma deficient in factors VII, VIII, IX, and XI but not in XII. Conclusions: Our results indicate that RMPs enhance primary hemostasis and both pathways of secondary hemostasis.

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia. There is currently no effective treatment for VCID. Resveratrol (RSV) is considered an antioxidant; however, our group has observed pleiotropic effects in stroke paradigms, suggesting more effects may contribute to mechanistic changes beyond antioxidative properties. The main goal of this study was to investigate if administering RSV twice a week could alleviate cognitive declines following the induction of a VCID model. Additionally, our aim was to further describe whether this treatment regimen could decrease cell death in brain areas vulnerable to changes in cerebral blood flow, such as the hippocampus and medial septum. We hypothesized RSV treatments in a mouse model of gradual cerebral hypoperfusion protect against cognitive impairment. We utilized gradual bilateral common carotid artery stenosis (GBCCAS) via the surgical implantation of ameroid constrictor devices. RSV treatment was administered on the day of implantation and twice a week thereafter. Cerebral perfusion was measured by laser speckle contrast imaging, and cognitive functions, including the recognition memory, the spatial working memory, and associative learning, were assessed by novel object recognition (NOR), Y-maze testing, and contextual fear conditioning (CFC), respectively. RSV treatment did not alleviate cerebral perfusion deficits but mitigated cognitive deficits in CFC and NOR after GBCCAS. Despite these deficits, no hippocampal pathology was observed; however, cholinergic cell loss in the medial septum was significantly increased after GBCCAS. This cholinergic cell loss was mitigated by RSV. This study describes a novel mechanism by which chronic RSV treatments protect against a VCID-induced cognitive decline through the preservation of cholinergic cell viability to improve memory performance.

Background: Cholinergic cells originating from the nuclei of the basal forebrain (BF) are critical for supporting various memory processes, yet BF cholinergic cell viability has not been explored in the context of focal cerebral ischemia. In the present study, we examined cell survival within several BF nuclei in rodents following transient middle cerebral artery occlusion. We tested the hypothesis that a previously established neuroprotective therapy—resveratrol preconditioning—would rescue BF cell loss, deficits in cholinergic-related memory performance, and hippocampal synaptic dysfunction after focal cerebral ischemia. Methods: Adult (2–3-month old) male Sprague-Dawley rats or wild-type C57Bl/6J mice were injected intraperitoneally with a single dose of resveratrol or vehicle and subjected to transient middle cerebral artery occlusion using the intraluminal suture method 2 days later. Histopathological, behavioral, and electrophysiological outcomes were measured 1-week post-reperfusion. Animals with reduction in cerebral blood flow <30% of baseline were excluded. Results: Cholinergic cell loss was observed in the medial septal nucleus and diagonal band of Broca following transient middle cerebral artery occlusion. This effect was prevented by resveratrol preconditioning, which also ameliorated transient middle cerebral artery occlusion–induced deficits in cognitive performance and hippocampal long-term potentiation. Conclusions: We demonstrate for the first time that focal cerebral ischemia induces cholinergic cell death within memory-relevant nuclei of the BF. The preservation of cholinergic cell viability may provide a mechanism by which resveratrol preconditioning improves memory performance and preserves functionality of memory-processing brain structures after focal cerebral ischemia.

Chronic diabetes may cause secondary complications like stroke and also increase post-stroke brain damage. In stroke research, the Stroke Therapy Academic Industry Roundtable (STAIR) identified criteria to increase translational value of preclinical studies, which highlighted the importance of using animal models of comorbidities. Numerous animal models have been used to study the aggravation of ischemic brain damage in diabetics. In this chapter, we discuss rat and mouse models of streptozotocin (STZ)-induced diabetes, with an efficient method provided. We also provide an overview of spontaneously diabetic rodent models. We present different pathophysiological features of diabetes in each rodent model along with the advantages and disadvantages of each model. Utilizing these models may aid the advancement of novel treatments and therapies to lower ischemic brain damage in patients of diabetes. Key words Diabetes Streptozotocin Type 1 diabetes Protocol