Exendin-4 ameliorates traumatic brain injury-induced cognitive impairment in rats.

Traumatic brain injury represents a major public health issue that affects 1.7 million Americans each year and is a primary contributing factor (30.5%) of all injury-related deaths in the United States. The occurrence of traumatic brain injury is likely underestimated and thus has been termed "a silent epidemic". Exendin-4 is a long-acting glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus that not only effectively induces glucose-dependent insulin secretion to regulate blood glucose levels but also reduces apoptotic cell death of pancreatic β-cells. Accumulating evidence also supports a neurotrophic and neuroprotective role of glucagon-like peptide-1 in an array of cellular and animal neurodegeneration models. In this study, we evaluated the neuroprotective effects of Exendin-4 using a glutamate toxicity model in vitro and fluid percussion injury in vivo. We found neuroprotective effects of Exendin-4 both in vitro, using markers of cell death, and in vivo, using markers of cognitive function, as assessed by Morris Water Maze. In combination with the reported benefits of ex-4 in other TBI models, these data support repositioning of Exendin-4 as a potential treatment for traumatic brain injury

Non-Steroidal Anti-Inflammatory Drugs in Alzheimer\u27s Disease and Parkinson\u27s Disease: Reconsidering the Role of Neuroinflammation

Alzheimer\u27s disease (AD) and Parkinson\u27s disease (PD) are the most common neurodegenerative diseases with age as the greatest risk factor. As the general population experiences extended life span, preparation for the prevention and treatment of these and other age-associated neurological diseases are warranted. Since epidemiological studies suggested that non-steroidal anti-inflammatory drug (NSAID) use decreased risk for AD and PD, increasing attention has been devoted to understanding the costs and benefits of the innate neuroinflammatory response to functional recovery following pathology onset. This review will provide a general overview on the role of neuroinflammation in these neurodegenerative diseases and an update on NSAID treatment in recent experimental animal models, epidemiological analyses, and clinical trials

Studies of Exendin-4 in vivo.

<p>Administration of Exendin-4 (Ex-4) significantly ameliorated cognitive impairments induced by fluid percussion-induced TBI in rats assessed by the Morris Water Maze (MWM) paradigm. (<b>A</b>) Time line of study: 30 min following fluid percussion injury-induced TBI or sham treatment, rats were administered either saline or Ex-4 for 7 days (initially, a loading dose of Ex-4 was administered followed by steady-state subcutaneous (s.c.) infusion via an implanted Alzet mini pump). Thereafter on days 10 to 14, animals were subjected to MWM assessment. (<b>B</b>). Post-injury administration of Ex-4 significantly improved MWM performance. Cognitive performance as assessed by latency to locate the hidden platform in the MWM was compared for each of the three treatment groups, TBI (<i>n</i> = 9), TBI+Ex-4 (<i>n</i> = 8), sham (<i>n</i> = 9). A repeated-measures ANOVA showed significant between group differences. Post hoc analysis using Fishers LSD revealed that animals that were treated with Ex-4 after TBI had significantly shorter latencies to reach the goal platform as compared to injured saline-treated. No significant difference was observed in the performance between TBI+Ex-4 and sham groups. Data are presented as the mean ± SEM. ***<i>p</i>≤ .001, sham relative to TBI. <b><i>^††</i></b><i>p</i>≤ .01, Ex-4 relative to TBI. (<b>C</b>) Number of platform zone crossings during the probe trial. Cumulative learning for the platform location was assessed during the probe trial as the number of times the animals swam within a 7.5 cm radius of the platform border (i.e., 2x the diameter of the platform). One-way ANOVA indicated significant between group differences. Fisher’s LSD post hoc showed that sham and TBI+Ex-4 had better retention of the platform location relative to animals that received TBI only. Data are presented as the mean ± SEM. Brackets indicate direct comparisons between groups. *<i>p</i>≤ .05, ***<i>p</i> ≤ .001.</p

Studies of Exendin-4 in vitro.

<p>Activation of GLP-1R signaling by Exendin-4 (Ex-4) protects both human SH-SY5Y cells and rat primary neurons from glutamate-induced excitotoxicity. (<b>A</b>) The cellular viability of SH-SY5Y cells challenged with glutamate (100 mM) was significantly reduced (37.5%) following 24 hr incubation, as assessed by MTS assay. Pretreatment with Ex-4 (100 nM) fully mitigated this glutamate-induced cellular loss (p<0.05 <i>vs</i>. glutamate alone challenged group, Dunnett’s <i>t</i>-test, N≥3 per treatment group). (<b>B</b>) In line with glutamate-induced excitotoxic cell loss, caspase-3 levels were significantly elevated in SH-SY5Y cells. Pretreatment with Exendin-4 fully ameliorated this rise (p<0.05 <i>vs</i>. glutamate alone challenged group, Dunnett’s T test, N≥3 per treatment group). (<b>C</b>) Co-treatment of SH-SY5Y cells with glutamate (100 mM) and concentrations as low as 10 nM Ex-4 resulted in significant mitigation of excitotoxicity, as assessed by MTS assay at 24 hr (p<0.05 <i>vs</i>. glutamate alone challenged group, Dunnett’s <i>t</i>-test, N≥3 per treatment group). (<b>D</b>) In parallel studies, rat primary neurons proved vulnerable to glutamate challenge (10 μM) which induced substantial apoptosis (73.1%). Pretreatment with Ex-4 (300 nM) significantly mitigated this, lowering levels to those of unchallenged control neuronal cultures (p<0.05 <i>vs</i>. glutamate alone challenged group, Dunnett’s <i>t</i>-test, N≥3 per treatment group). The glutamate challenge concentrations (100 mM for SH-SY5Y cells and 10 μM for primary neurons) and time line were selected from preliminary studies focused on inducing a significant yet incomplete cellular loss to allow for assessment of mitigation as well as a potential intensification of cell death by the experimental treatment.</p