Orexin-A Suppresses Postischemic Glucose Intolerance and Neuronal Damage through Hypothalamic Brain-Derived Neurotrophic Factor

Abstract

Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N9-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A.

RETRACTED ARTICLE: Effects of BDNF-Transfected BMSCs on Neural Functional Recovery and Synaptophysin Expression in Rats with Cerebral Infarction

“…BDNF, brain-derived neurotrophic factor BDNF brain-derived neurotrophic factor a Compared with the sham group at the same time point, P < 0.05 b Compared with the non-BDNF model group at the same time point, P < 0.05 dendritic growth, and axonal branching [30,31]. BDNF has been reported to have a neuroprotective effect against brain injury and is thought to be potent candidates in the recovery from cerebral ischemia [32,33]. BDNF could support the neuron survival and encourage neuron and synapse growth and differentiation, and is related to neuroplasticity and contributes to neural rehabilitation after stroke [34].…”

Hepatic Branch Vagus Nerve Plays a Critical Role in the Recovery of Post-Ischemic Glucose Intolerance and Mediates a Neuroprotective Effect by Hypothalamic Orexin-A

“…The selective non-peptide orexin-1 receptor antagonist inhibitor, N -(2-methyl-6-benzoxazolyl)- N ′-1,5-naphthyridin-4-yl urea (SB334867) (Tocris Bioscience, St. Louis, MO, USA), was dissolved in 1% DMSO and administered (intramedullary; 50 or 200 pmol/mouse) 30 min before saline or orexin-A intra-hypothalamic administration. The orexin-A and SB334867 doses and the experimental schedule used here were chosen based on our previous publication [8]. All intra-hypothalamic administrations were performed as previously reported [8], [23], [24].…”

“…administration of orexin-A [21]. In our previous reports, intrahypothalamic administration of orexin-A suppressed cerebral ischemic neuronal damage by regulating post-ischemic glucose intolerance, which was achieved by improving impaired hepatic insulin signaling [8]. In other reports, orexin-positive fibers are shown to be distributed throughout the brainstem, including in neurons of the dorsal motor nucleus of the vagus, which is the major source of parasympathetic innervation to peripheral tissues (such as the liver), and neurons in the nucleus of solitary tract (NTS) [18], [19], [22].…”

“…Past studies have also suggested that hyperglycemia and/or glucose intolerance following stroke may be associated with greater mortality and reduced functional recovery [5], [6]. In a focal cerebral ischemic model, post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage [7], [8], [9]. However, the mechanisms remain unclear.…”

Targeting the orexinergic system: Mainly but not only for sleep-wakefulness therapies

“…Regulation of appetite and stress response [24][25][26] Respiratory effects [27][28][29] Addiction 11,25,26,[30][31][32][33][34][35][36][37][38] Behavioral changes associated with cocaine administration 39 Analgesia 11,40 Food intake regulation 23,41 Central regulation of feeding (of blind cavefish) 42 Regulation of glucose metabolism 43,44 Energy balance regulation 45,46 Insulin secretion regulation 44 Variability in diet-induced obesity sensitivity 47 Proliferation and viability of 3T3-L1 preadipocytes 48 Body temperature regulation 46,49 Neuroendocrine function 6,49,50 Pituitary hormone secretion 51 Cardiovascular activities 49,[52][53][54] Post-ischemic attenuation of inflammatory responses (neuroprotection) 55 Prevention of cerebral ischemic neuronal damage (neuroprotection) 43 Reproduction [56][57]…”