ABSTRACT
Exposure to intermittent hypoxia (IH) is associated with cognitive impairments and oxidative stress in brain regions involved in learning and memory. In earlier studies, erythropoietin (EPO) showed a neuroprotective effect in large doses. The aim of the present study was to explore the effect of smaller doses of EPO, such as those used in the treatment of anemia, on IH-induced cognitive deficits and hippocampal oxidative stress in young rats. The effect of concurrent EPO treatment (500 and 1,000 IU/kg/day ip) on spatial learning and memory deficits induced by long-term exposure to IH for 6 weeks was tested using the Morris water maze (MWM) test and the elevated plus maze (EPM) test. Moreover, the effect on hippocampal glutamate and oxidative stress were assessed. Exposure to IH induced a significant impairment of spatial learning and cognition of animals in both MWM and EPM performance parameters. Moreover, hippocampal glutamate and thiobarbituric acid reactive substances (TBARS) increased while antioxidant defenses (GSH and GSH-Px) decreased. EPO in the tested doses significantly reduced the IH-induced spatial learning deficits in both MWM and EPM tests and dose-dependently antagonized the effects of IH on hippocampal glutamate, TBARS, GSH levels, and GSH-Px activity. Treatment with EPO in moderate doses that used for anemia, concurrently with IH exposure can antagonize IH-induced spatial learning deficits and protect hippocampal neurons from IH-induced lipid peroxidation and oxidative stress-induced damage in young rats, possibly through multiple mechanisms involving a potential antioxidative effect.
Subject(s)
Erythropoietin/administration & dosage , Erythropoietin/antagonists & inhibitors , Hypoxia/psychology , Animals , Epoetin Alfa , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Hippocampus/drug effects , Hypoxia/physiopathology , Male , Maze Learning/drug effects , Memory Disorders/complications , Oxidative Stress/drug effects , Rats , Recombinant Proteins/administration & dosageABSTRACT
UNLABELLED: The aim of the present study was to explore the potential protective effect of Ginkgo biloba extract (EGb 761) on intermittent hypoxia (IH)-induced memory deficits and oxidative stress in rats. METHODS: The passive avoidance reflex (PAR) test was employed to assess the effect of concurrent EGb 761 treatment in different dose levels on the memory deficits that were induced by concurrent long-term exposure to IH (21 days). The levels of hippocampal malondialdehyde (MDA), nitric oxide (NO), and intracellular glutathione (GSH) and the activity of glutathione peroxidase (GSH-Px) were estimated. In addition, serum and hippocampal 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were assessed to study the effect of EGb 761 on hippocampal oxidative DNA damage induced by IH. RESULTS: Exposure to long-term IH in rats induced marked memory impairment that was indicated by a significant decrease in the retention latency in the PAR test. This effect was accompanied by a significant increase in hippocampal oxidative stress and DNA damage. EGb 761 that was administered in either 50- or 100-mg/kg doses per day reversed IH-induced memory deficits, an effect that was accompanied by a significant decrease in hippocampal MDA and NO levels. The antioxidant defence (GSH and GSH-Px) that was depressed by IH was significantly reactivated by EGb 761. Furthermore, serum and hippocampal levels of 8-OHdG that were elevated by IH were significantly reduced. CONCLUSIONS: EGb 761 can protect against IH-induced memory impairment, oxidative stress and neuronal DNA damage, possibly through multiple mechanisms involving its potential anti-oxidative effect.
Subject(s)
DNA Damage/drug effects , Ginkgo biloba/chemistry , Memory Disorders/drug therapy , Phytotherapy , Plant Extracts/pharmacology , Protective Agents/pharmacology , 8-Hydroxy-2'-Deoxyguanosine , Animals , Antioxidants/analysis , Antioxidants/metabolism , Avoidance Learning/drug effects , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/analysis , Deoxyguanosine/metabolism , Glutathione/analysis , Glutathione/metabolism , Hippocampus/metabolism , Hypoxia/complications , Lipid Peroxidation/drug effects , Male , Memory Disorders/etiology , Oxidative Stress , Plant Extracts/administration & dosage , Plant Extracts/therapeutic use , Protective Agents/administration & dosage , Protective Agents/therapeutic use , Rats , Rats, WistarABSTRACT
In this study, we tested the effect of urocortin 1 (Ucn1) on the contractility of gallbladder smooth muscle (GBSM) strips from guinea pigs and studied the involvement of corticotropin-releasing factor (CRF) receptors in this effect. The effect of Ucn1 on the isometric contractions of non-contracted and acetylcholine (Ach)-contracted GBSM, and the effects of CRF-R antagonists antalarmin and astressin 2B on the effect of Ucn1 were studied. In addition, the expression of receptors for CRF-R1 and CRF-R2 in guinea pig gallbladder were investigated using reverse transcription - polymerase chain reaction (RT-PCR). Ucn1 dose-dependently inhibited the contractility of GBSM. Moreover, Ucn1 decreased the resting tension, the mean contractile amplitude, and the contractile frequency in both non-contracted and Ach-contracted strips of GBSM. Furthermore, Ucn1 induced rightward shift of the Ach concentration-response curve of Ach in Ach-contracted strips. This inhibitory effect of Ucn1 on both non-contracted and Ach-contracted strips was inhibited by astressin 2B, but not by antalarmin. RT-PCR demonstrated that the CRF-R2, but not CRF-R1 receptor subtype is expressed in the muscularis muscle of guinea pig gallbladder. In conclusion, Ucn1 has an inhibitory effect on the contractility of GBSM of guinea pig, mediated through stimulating CRF-R2 receptors in GBSM. More studies are needed to clarify the intracellular signaling events involved in this effect.
