Intranasal insulin helps overcome brain insulin deficiency and improves survival and post-stroke cognitive impairment in male mice.

Obesity increases the risk for stroke and is associated with worse post-stroke outcomes; however, the mechanisms are poorly understood. Diet-induced obesity leads to insulin resistance and subsequently, brain insulin deficiency. The purpose of this study was to investigate the potential impact of brain insulin deficiency on post-stroke outcomes. To accomplish this, brain insulin levels were assessed in male C57BL/6J (B6) mice placed on either a standard diet or 54% kcal high-fat diet, a known model of insulin resistance. Mice were subjected to either a sham surgery (control) or 30-min middle cerebral artery occlusion to induce an ischemic stroke and administered either intranasal saline (0.9%) or intranasal insulin (1.75 U) twice daily for 5 days beginning on day 1 post-stroke. High-fat diet-induced brain insulin deficiency was associated with increased mortality, neurological and cognitive deficits. On the other hand, increasing brain insulin levels via intranasal insulin improved survival, neurological and cognitive function in high-fat diet mice. Our data suggests that brain insulin deficiency correlates with worse post-stroke outcomes in a diet-induced mouse model of insulin resistance and increasing brain insulin levels may be a therapeutic target to improve stroke recovery.

Brain-Derived Neurotrophic Factor and Nerve Growth Factor Therapeutics for Brain Injury: The Current Translational Challenges in Preclinical and Clinical Research.

Ischemic stroke and traumatic brain injury (TBI) are among the leading causes of death and disability worldwide with impairments ranging from mild to severe. Many therapies are aimed at improving functional and cognitive recovery by targeting neural repair but have encountered issues involving efficacy and drug delivery. As a result, therapeutic options for patients are sparse. Neurotrophic factors are one of the key mediators of neural plasticity and functional recovery. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) serve as potential therapeutic options to increase neural repair and recovery as they promote neuroprotection and regeneration. BDNF and NGF have demonstrated the ability to improve functional recovery in preclinical and to a lesser extent clinical studies. Direct and indirect methods to increase levels of neurotrophic factors in animal models have been successful in improving postinjury outcome measures. However, the translation of these studies into clinical trials has been limited. Preclinical experiments have largely failed to result in significant impacts in clinical research. This review will focus on the administration of these neurotrophic factors in preclinical and clinical stroke and TBI and the challenges in translating these therapies from the bench to the clinic.

Obesity-related cognitive impairment: The role of endothelial dysfunction.

Obesity is a global pandemic associated with macro- and microvascular endothelial dysfunction. Microvascular endothelial dysfunction has recently emerged as a significant risk factor for the development of cognitive impairment. In this review, we present evidence from clinical and preclinical studies supporting a role for obesity in cognitive impairment. Next, we discuss how obesity-related hyperinsulinemia/insulin resistance, systemic inflammation, and gut dysbiosis lead to cognitive impairment through induction of endothelial dysfunction and disruption of the blood brain barrier. Finally, we outline the potential clinical utility of dietary interventions, exercise, and bariatric surgery in circumventing the impacts of obesity on cognitive function.

D-Amphetamine Exposure Differentially Disrupts Signaling Across Ontogeny in the Zebrafish.

Background: Prescriptive and illicit amphetamine (AMPH) use continues to increase along with the likelihood that during an individual's lifetime, the drug deleteriously influences the growth and connectivity of behavior circuits necessary for survival. Throughout ontogeny, neural circuits underlying these behaviors grow in complexity, gradually integrating many sensory inputs that trigger higher order coordinated motor responses. In the present study, we examine how AMPH disrupts the establishment of these circuits at critical neurodevelopmental periods, as well as the communication among established survival circuits. Materials and Methods: Zebrafish embryos (from 1 hpf) were raised in AMPH solutions, growth parameters and escape behavior were assessed at 24 and 48 hpf, and spinal cord tissues analyzed for differences in excitatory-inhibitory signaling balance among treatments. Adult fish were fed an acute dosage of AMPH over an 11-day conditioned place preference (PP) paradigm during which behaviors were recorded and brain tissues analyzed for alterations in dopaminergic signaling. Results: AMPH negatively affects embryonic growth and slows the execution of escape behavior, suggesting an imbalance in locomotor signaling. Although local spinal circuits provide primary escape modulation, no differences in inhibitory glycinergic, and excitatory glutamatergic signaling were measured among spinal neurons. AMPH also influenced place preference in adult zebrafish and resulted in the increased expression of dopamine signaling proteins (DRD1) in brain areas governing survival behaviors.