exenatide and Hypoxia-Ischemia--Brain

Hypoxic-ischemic encephalopathy is brain injury resulting from the loss of oxygen and blood supply around the time of birth. It is associated with a high risk of death or disability. The only approved treatment is therapeutic hypothermia. Therapeutic hypothermia has consistently been shown to significantly reduce the risk of death and disability in infants with hypoxic-ischemic encephalopathy. However, approximately 29% of infants treated with therapeutic hypothermia still develop disability. Recent preclinical and clinical studies have shown that there is still persistent neuroinflammation even after treating with therapeutic hypothermia, which may contribute to the deficits seen in infants despite treatment. This suggests that potentially targeting this persistent neuroinflammation would have an additive benefit in addition to therapeutic hypothermia. A potential additive treatment is Exendin-4, which is a glucagon-like peptide 1 receptor agonist. Preclinical data from various in vitro and in vivo disease models have shown that Exendin-4 has anti-inflammatory, mitochondrial protective, anti-apoptotic, anti-oxidative and neurotrophic effects. Although preclinical studies of the effect of Exendin-4 in perinatal hypoxic-ischemic brain injury are limited, a seminal study in neonatal mice showed that Exendin-4 had promising neuroprotective effects. Further studies on Exendin-4 neuroprotection for perinatal hypoxic-ischemic brain injury, including in large animal translational models are warranted to better understand its safety, window of opportunity and effectiveness as an adjunct with therapeutic hypothermia.

Topics: Animals; Brain Injuries; Exenatide; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Mice; Neuroinflammatory Diseases; Pregnancy

Hypoxic-ischaemic encephalopathy remains a global health burden. Despite medical advances and treatment with therapeutic hypothermia, over 50% of cooled infants are not protected and still develop lifelong neurodisabilities, including cerebral palsy. Furthermore, hypothermia is not used in preterm cases or low resource settings. Alternatives or adjunct therapies are urgently needed. Exendin-4 is a drug used to treat type 2 diabetes mellitus that has also demonstrated neuroprotective properties, and is currently being tested in clinical trials for Alzheimer's and Parkinson's diseases. Therefore, we hypothesized a neuroprotective effect for exendin-4 in neonatal neurodisorders, particularly in the treatment of neonatal hypoxic-ischaemic encephalopathy. Initially, we confirmed that the glucagon like peptide 1 receptor (GLP1R) was expressed in the human neonatal brain and in murine neurons at postnatal Day 7 (human equivalent late preterm) and postnatal Day 10 (term). Using a well characterized mouse model of neonatal hypoxic-ischaemic brain injury, we investigated the potential neuroprotective effect of exendin-4 in both postnatal Day 7 and 10 mice. An optimal exendin-4 treatment dosing regimen was identified, where four high doses (0.5 µg/g) starting at 0 h, then at 12 h, 24 h and 36 h after postnatal Day 7 hypoxic-ischaemic insult resulted in significant brain neuroprotection. Furthermore, neuroprotection was sustained even when treatment using exendin-4 was delayed by 2 h post hypoxic-ischaemic brain injury. This protective effect was observed in various histopathological markers: tissue infarction, cell death, astrogliosis, microglial and endothelial activation. Blood glucose levels were not altered by high dose exendin-4 administration when compared to controls. Exendin-4 administration did not result in adverse organ histopathology (haematoxylin and eosin) or inflammation (CD68). Despite initial reduced weight gain, animals restored weight gain following end of treatment. Overall high dose exendin-4 administration was well tolerated. To mimic the clinical scenario, postnatal Day 10 mice underwent exendin-4 and therapeutic hypothermia treatment, either alone or in combination, and brain tissue loss was assessed after 1 week. Exendin-4 treatment resulted in significant neuroprotection alone, and enhanced the cerebroprotective effect of therapeutic hypothermia. In summary, the safety and tolerance of high dose exendin-4 administrations, combined with its

Topics: Animals; Animals, Newborn; Brain; Disease Models, Animal; Exenatide; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Mice; Neuroprotective Agents

Transient global ischemia induces selective hippocampal pyramidal neuronal death. Under conditions of severe ischemic hypoxia, hypoxia-inducible factor-1α (HIF-1α) induces apoptosis. Exendin-4 (Ex-4), the glucagon-like peptide-1 receptor (GLP-1R) agonist, provides neuroprotection against brain damage after cerebral ischemia. We investigated the relationship between Ex-4 and HIF-1α by examining Ex-4-induced changes in HIF-1α expression in the gerbil hippocampus following global brain ischemia (in vivo) and in neuroblastoma cells (SH-SY5Y) and cortical primary neurons (in vitro). Twice-daily administration of Ex-4 (1 μg/kg) for 3 days after ischemia (30 min before and 30 min after ischemia on the day of surgery and 2 more days) decreased the number of Fluoro-Jade B-stained cells in the CA1 pyramidal region of the hippocampus of the ischemic brain. Western blot analysis indicated a significant decrease in HIF-1α expression in the ischemic compared with the Sham brain following Ex-4 treatment. These in-vivo results were confirmed in vitro in SH-SY5Y cells and primary cortical neurons treated with 100 nM of Ex-4 under hypoxic conditions (0.1%>O2). We found that Ex-4 decreased the HIF-1α expression in the SH-SY5Y cell line and primary cortical neurons under hypoxic conditions, and this effect was reversed by cotreatment with exendin (9-39), a GLP-1R antagonist. These results suggest that HIF-1α may be involved in the neuroprotective effect of Ex-4 in the hypoxia-damaged brain.

Topics: Animals; CA1 Region, Hippocampal; Cell Line, Tumor; Exenatide; Gerbillinae; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Ischemia, Brain; Neurons; Neuroprotective Agents; Peptides; Venoms