Chronic kidney disease (CKD) is a major public health problem worldwide and is associated with spatial learning deficits. The aim of the present study was to evaluate the protective effects of hydrogen sulfide (H2S) on CKD-mediated behavioral deficits with emphasis to the role of nitric oxide (NO) in these effects. Fifty rats were randomly allocated to five experimental groups including: sham, Five-sixth (5/6) nephrectomy (Nx), 5/6Nx + NaHS, 5/6Nx + NaHS+L-nitroarginine methyl ester (L-NAME), and 5/6Nx + NaHS+aminoguanidine (AMG). Twelve weeks after 5/6Nx, we evaluated proteinuria, creatinine clearance (CrCl), oxidative/antioxidant status, and hippocampus neuro-inflammation and NO synthase genes in all groups. Furthermore, training trials of all animals were conducted in the Morris water maze (MWM) task one day before animal euthanizing. As predicted, 5/6Nx induced several injuries, including enhancement of proteinuria and reduction of CCr, oxidant/antioxidant imbalance and up-regulation of TNF-α and IL-1β gene expressions in the hippocampus tissues. As predicted, 5/6Nx resulted in learning and memory impairments, and increased escape latency during acquisition trials in the MWM task. Interestingly, NaHS (H2S donor) improved behavioral deficits, renal dysfunction, accelerated anti-oxidant/anti-inflammatory responses and increased eNOS and decreased iNOS. Moreover, these effects of NaHS were prevented by L-NAME but not AMG co-administration. In conclusion, H2S ameliorates CKD-mediated brain dysfunctions, through interaction with NO signaling in the hippocampus.
It is very important to investigate the neurotoxic effects of metals on learning and memory processes. In this study, we tried to investigate the effects and time course properties of oral administration of zinc chloride (25, 50, and 75 mg/kg, for 2 weeks), lead acetate (250, 750, 1,500, and 2,500 ppm for 4, 6 and 8 weeks), and their possible mechanisms on a model of memory function. For this matter, we examined the intra-peritoneal injections of nicotine (0.25, 0.5, 1, and 1.5 mg/kg) and bucladesine (50, 100, 300, and 600 nM/mouse) for 4 days alone and in combination with mentioned metals in the step-through passive avoidance task. Control animals received saline, drinking water, saline, and DMSO (dimethyl sulfoxide)/deionized water (1:9), respectively. At the end of each part of studies, animals were trained for 1 day in step-through task. The avoidance memory retention alterations were evaluated 24 and 48 h later in singular and combinational studies. Zinc chloride (75 mg/kg) oral gavage for 2 weeks decreased latency times compared to control animals. Also, lead acetate (750 ppm oral administrations for 8 weeks) caused significant lead blood levels and induced avoidance memory retention impairments. Four-days intra-peritoneal injection of nicotine (1 mg/kg) increased latency time compared to control animals. Finally, findings of this research showed that treatment with intra-peritoneal injections of nicotine (1 mg/kg) and/or bucladesine (600 nM/mouse) reversed zinc chloride- and lead acetate-induced avoidance memory retention impairments. Taken together, these results showed the probable role of cholinergic system and protein kinase A pathways in zinc chloride- and lead acetate-induced avoidance memory alterations.
Accumulated evidence shows that the cAMP and cGMP signaling pathway plays an important role in memory function and neuronal plasticity. Phosphodiesterase 5 (PDE5) is a hopeful therapeutic target in AD (Alzheimer disease), and PDE5 inhibition may be a good therapeutic strategy for the treatment of AD. In the present study, the four-day bilateral intra-hippocampal infusion of H-89 as a protein kinase AII inhibitor (10 µM/side) and intra-peritoneal injections of tadalafil (20 mg/kg) and scopolamine (0.5 mg/kg) alone and also on combination on spatial learning in Morris water maze (MWM) were investigated. DMSO and saline were used as controls for H-89 and other mentioned drugs, respectively. Rats were trained for 4 days; each day included one block of four trials. Post- training probe trial tests were performed on day 5. Administration of H-89 and scopolamine led to a significant impairment in spatial learning compared to their related controls. But, combination of tadalafil/H-89 or tadalafil/scopolamine reversed H-89 or scopolamine- induced spatial learning deficits in MWM. Taken together, these results showed the probable regulatory effects of cGMP on cholinergic and cAMP/PKA signaling pathways in co-administrations of these mentioned drugs on spatial learning in MWM.
Quercetin and resveratrol are found in a variety of fruits and vegetables and have several biological and pharmacological properties. In this study, the effects of quercetin [50 mg/kg, intraperitoneal (i.p.)] and resveratrol (50 mg/kg, i.p.) on zinc chloride (ZnCl2; 75 mg/kg/d, 2 weeks oral gavage) and sodium metavanadate (SMV; 22.5 mg/kg/d, 2 weeks oral gavage) induced passive avoidance memory retention were investigated in step-through passive avoidance tasks. ZnCl2 was dissolved in saline and SMV was dissolved in drinking water. Mice received ZnCl2 or SMV orally for two weeks and were administered quercetin or resveratrol by i.p. injection on day 14, days 12 and 14, or days 10, 12, and 14. At the end of treatment, animals were trained for one day in a step-through passive avoidance task, then alterations in avoidance memory retention were evaluated after 24, 48, 96, and 168 h. Oral consumption of ZnCl2 and SMV decreased latency time compared with control groups. Both quercetin and resveratrol (50 mg/kg, i.p.) prevented ZnCl2-and SMV-induced avoidance memory retention impairments and did not significantly alter muscle strength, as demonstrated in rotarod tasks. No significant differences were observed between mice who received single, double, or triple doses of quercetin or resveratrol. The results suggest that quercetin and resveratrol may have preventive effects on ZnCl2-and SMV-induced memory impairment in male mice.
Objectives H-89 (a protein kinase AII [PKA II] inhibitor) impairs the spatial memory in the Morris water maze task in rats. In the present study, we aimed to study the protective effects of nicotine and O-acetyl-L-carnitine against H-89-induced spatial memory deficits. Methods Spatial memory impairment was induced by the bilateral intrahippocampal administration of 10 µM H-89 (dissolved in dimethyl sulfoxide, DMSO) to rats. The rats then received bilateral administrations of either nicotine (1 μg/μL, dissolved in saline) or O-acetyl-L-carnitine (100 μM/side, dissolved in deionized water) alone and in combination. Control groups received either saline, deionized water, or DMSO. Results The H-89-treated animals showed significant increases in the time and distance travelled to find hidden platforms, and there was also a significant decrease in the time spent in the target quadrant compared to DMSO-treated animals. Nicotine and O-acetyl-L-carnitine had no significant effects on H-89-induced spatial learning impairments alone, but the bilateral intrahippocampal co-administration of nicotine and O-acetyl-L-carnitine prevented H-89-induced spatial learning deficits and increased the time spent in the target quadrant in comparison with H-89-treated animals. Conclusions Our results indicated the potential synergistic effects of nicotine and O-acetyl-L-carnitine in preventing protein kinase AII inhibitor (H-89)-induced spatial learning impairments.
Zinc, an essential micronutrient and biochemical element of the human body, plays structural, catalytic, and regulatory roles in numerous physiological functions. In the current study, the effects of a pretraining oral administration of zinc chloride (10, 25, and 50 mg/kg) for 14 consecutive days and post-training bilateral intra-hippocampal infusion of 1400W as a selective inducible nitric oxide synthase (iNOS) inhibitor (10, 50, and 100 μM/side), alone and in combination, on the spatial memory retention in Morris water maze (MWM) were investigated. Animals were trained for 4 days and tested 48 h after completion of training. Also, the molecular effects of these compounds on the expression of choline acetyltransferase (ChAT), as a cholinergic marker in the CA1 region of the hippocampus and medial septal area (MSA), were evaluated. Behavioral and molecular findings of this study showed that a 2-week oral administration of zinc chloride (50 mg/kg) impaired spatial memory retention in MWM and decreased ChAT expression. Immunohistochemical analysis of post-training bilateral intra-hippocampal infusion of 1400W revealed a significant increase in ChAT immunoreactivity. Furthermore, post-training bilateral intra-hippocampal infusion of 1400W into the CA1 region of the hippocampus reversed zinc chloride-induced spatial memory impairment in MWM and significantly increased ChAT expression in comparison with zinc chloride-treated animals. Taken together, these results emphasize the role of selective iNOS inhibitors in reversing zinc chloride-induced spatial memory deficits via modulation of cholinergic marker expression.
Background: Vanadium is a potential neurotoxic agent widely distributed in the environment. Understanding the neurotoxic mechanisms of vanadium on learning and memory seems necessary. Methods: We investigated the time-dependent (1-week, 2- week and 4-week) effects of sodium metavanadate (SMV) (25 mg/kg/day; pre-training oral administration) and 4-day intraperitoneal injections of aminoguanidine (AG) as a selective inducible nitric oxide synthase inhibitor (10, 50, and 100 mg/kg) on spatial memory retention in Morris water maze. Animals were trained for 4 days and tested 48 h after the last training trial. Results: The data showed that 4-week oral pre-treatment with SMV (25 mg/kg/day) induced spatial memory retention deficits and decreased the time spent in the target quadrant. We found that 4-day administration of different doses of AG during training trials significantly decreased the time and distance of finding the hidden platforms. Additionally, SMV-induced spatial memory retention impairments were prevented in animals received combined SMV (25 mg/kg/day, 4 weeks) and AG (10 mg/kg/day, 4 days). Conclusion: Our findings showed the protective role of AG on SMV-induced spatial memory retention deficits.
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