Opposite effects of central oxytocin and arginine vasopressin on changes in gastric motor function induced by chronic stress.

Hypothalamic oxytocin (OXT) and arginine vasopressin (AVP) are known to act oppositely on hypothalamic-pituitary-adrenal (HPA) axis, stress response and gastrointestinal (GI) motility. In rodents, exposure to restraint stress (RS) delays gastric emptying (GE), however, repeated exposure to the same stressor (chronic homotypic stress (CHS)), the delayed GE is restored to basal level, while hypothalamic OXT is upregulated. In contrast, when rats are exposed to chronic heterotypic stress (CHeS), these adaptive changes are not observed. Although the involvement of central OXT in gastric motor adaptation is partly investigated, the role of hypothalamic AVP in CHeS-induced maladaptive paradigm is poorly understood. Using in-vivo brain microdialysis in rats, the changes OXT and AVP release from hypothalamus were monitored under basal non-stressed (NS) conditions and in rats exposed to acute stress (AS), CHS and CHeS. To investigate the involvement of central endogenous OXT or AVP in CHS-induced habituation and CHeS-induced maladaptation, chronic central administration of selective OXT receptor antagonist L-371257 and selective AVP V1b receptor antagonist SSR-149415 was performed daily. OXT was measured higher in AS and CHS group, but not in CHeS-loaded rats, whereas AVP significantly increased in rats exposed to AS and CHeS. Additionally, the response of the hypothalamic OXT- and AVP-producing cells was amplified following CHS and CHeS, respectively. In rats exposed to AS for 90min solid GE significantly delayed. The delayed-GE was completely restored to the basal level following CHS, however, it remained delayed in CHeS-loaded rats. The CHS-induced restoration was prevented by L-371257, whereas SSR-149415 abolished the CHeS-induced impaired GE. A significant correlation was observed between GE and (i) OXT in CHS-loaded rats (rho=0.61, p<0.05, positively), (ii) AVP in CHeS-loaded rats (rho=0.69, p<0.05, negatively). Under long term stressed conditions, the release of AVP and OXT from hypothalamus may vary depending on the content of the stressors. Central AVP appears to act oppositely to OXT by mediating CHeS-induced gastric motor maladaptation. Long term central AVP antagonism might be a pharmacological approach for the treatment of stress-related gastric motility disorders.

Gastroprotective effect of orexin-A and heme oxygenase system.

BACKGROUND: Orexin-A, besides playing an important role in the mechanism of food intake, exhibits a potent gastroprotective action against the formation of acute gastric mucosal injury. The aim of the present study was to determine the effect of administered orexin-A against ischemia-reperfusion (I/R)-induced gastric injury on the expression of heme oxygenase (HO)-1 and HO-2 in gastric tissue. MATERIALS AND METHODS: Wistar rats were subjected to 30 min of ischemia followed by 3 h reperfusion. Orexin-A was infused at a dose of 500 pmol/kg/min during the I/R period. The lesion area was measured by stereomicroscope. The myeloperoxidase activity and 4-hydroxinonenol-malondialdehyde content of gastric mucosa were evaluated spectrophotometrically, and the gastric tumor necrosis factor-α was measured by enzyme linked immune sorbent assay. The expression of HO-1 and HO-2 was determined by Western blotting analysis. RESULTS: Orexin-A significantly decreased the I/R-induced gastric lesions, myeloperoxidase activity, and 4-hydroxinonenol-malondialdehyde concentration in gastric tissue exposed to I/R. The gastroprotective effect of orexin-A in gastric I/R model was accompanied by the increase in HO-2 expression and the decrease in HO-1 expression. CONCLUSIONS: Orexin-A exerts a protective action on gastric mucosa subjected to I/R, and this effect is associated with the reduction of neutrophil infiltration and lipid peroxidation in gastric tissue in addition to the increase in HO-2 expression due to the administration of orexin-A.

Mechanism of the beneficial effect of melatonin in experimental Parkinson's disease.

This study aimed to elucidate locomotor activity changes in 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) and investigate the possible beneficial effects of melatonin on altered levels of locomotor activity, cyclooxygenase (COX), prostaglandin E2 (PGE2), nuclear factor kappa-B (NF-κB), nitrate/nitrite and apoptosis. Male Wistar rats were divided into five groups: vehicle (V), melatonin-treated (M), 6-OHDA-injected (6-OHDA), 6-OHDA-injected + melatonin-treated (6-OHDA-Mel) and melatonin treated + 6-OHDA-injected (Mel-6-OHDA). Melatonin was administered intraperitoneally at a dose of 10 mg/kg/day for 30 days in M and Mel-6-OHDA groups, for 7 days in 6-OHDA-Mel group. Experimental PD was created stereotactically via unilateral infusion of 6-OHDA into the medial forebrain bundle (MFB). The 6-OHDA-Mel group started receiving melatonin when experimental PD was created and treatment was continued for 7 days (post-treatment). In the Mel-6-OHDA group, experimental PD was created on the 23rd day of melatonin treatment and continued for the remaining 7 days (pre- and post-treatment). Locomotor activity performance decreased in 6-OHDA group compared with vehicle; however melatonin treatment did not improve this impairment. Nuclear factor kappa Bp65 and Bcl-2 levels were significantly decreased while COX, PGE2 and caspase-3 activity were significantly increased in 6-OHDA group. Melatonin treatment significantly decreased COX, PGE2 and caspase-3 activity, increased Bcl-2 and had no effect on NF-κB levels in experimental PD. 6-Hydroxydopamine injection caused an obvious reduction in TH positive dopaminergic neuron viability as determined by immunohistochemistry. Melatonin supplementation decreased dopaminergic neuron death in 6-OHDA-Mel and Mel-6-OHDA groups compared with 6-OHDA group. Melatonin also protected against 6-OHDA-induced apoptosis, as identified by increment in Bcl-2 levels in dopaminergic neurons. The protective effect of melatonin was more prominent for most parameter following 30 days treatment (pre- and post-) than 7 days post-treatment. In summary, melatonin treatment decreased dopaminergic neuron death in experimental PD model by increasing Bcl-2 protein level and decreasing caspase-3 activity.