Therapeutic Potential of Pentoxifylline in Paraquat-Induced Pulmonary Toxicity: Role of the Phosphodiesterase Enzymes.

Pentoxifylline (PTX), a non-selective phosphodiesterase inhibitor, has demonstrated protective effects against lung injury in animal models. Given the significance of pulmonary toxicity resulting from paraquat (PQ) exposure, the present investigation was designed to explore the impact of PTX on PQ-induced pulmonary oxidative impairment in male mice.Following preliminary studies, thirty-six mice were divided into six groups. Group 1 received normal saline, group 2 received a single dose of PQ (20 mg/kg; i.p.), and group 3 received PTX (100 mg/kg/day; i.p.). Additionally, treatment groups 4-6 were received various doses of PTX (25, 50, and 100 mg/kg/day; respectively) one hour after a single dose of PQ. After 72 hours, the animals were sacrificed, and lung tissue was collected.PQ administration caused a significant decrease in hematocrit and an increase in blood potassium levels. Moreover, a notable increase was found in the lipid peroxidation (LPO), nitric oxide (NO), and myeloperoxidase (MPO) levels, along with a notable decrease in total thiol (TTM) and total antioxidant capacity (TAC) contents, catalase (CAT) and superoxide dismutase (SOD) enzymes activity in lung tissue. PTX demonstrated the ability to improve hematocrit levels; enhance SOD activity and TTM content; and decrease MPO activity, LPO and NO levels in PQ-induced pulmonary toxicity. Furthermore, these findings were well-correlated with the observed lung histopathological changes.In conclusion, our results suggest that the high dose of PTX may ameliorate lung injury by improving the oxidant/antioxidant balance in animals exposed to PQ.

The Role of Cyclooxygenase 2 in the Cognitive Impairment Induced by Alcohol or Stress in Rats.

BACKGROUND: Cognitive impairment is an unpleasant and progressive mental disorder characterized by learning and memory disabilities. Stress and alcohol are two known environmental factors that increase cognitive impairment. This study was designed to evaluate the relative role of cyclooxygenase 2 in alcohol or stress-induced cognitive impairment. MATERIALS AND METHODS: Male Wistar rats were randomly divided into groups with six rats in each. The groups included sham, control, alcohol (15% ethanol in drinking water), and restraint stress (restraint 6 h per day). Three separated groups received celecoxib at a dose of 20 mg/kg in addition to those listed above. The treatments continued daily for 28 days. The object recognition task (ORT) and Morris water maze (MWM) are used to evaluate the learning and memory. RESULTS: Alcohol or restrain stress significantly increased the time and distance needed to find the hidden platform in MWM. Furthermore, they decreased the recognition index in ORT compared to the control group. Administration of celecoxib significantly decreased the required time and traveled distance to reach the platform in alcohol-treated animals but not in the stress-exposed rats. Celecoxib also significantly increased the recognition index both in alcohol- or restraint stress-exposed animals. CONCLUSION: We found that either alcohol or restraint stress impairs memory in rats. In MWM, celecoxib improved the alcohol-induced memory impairment but could not show a reduction in memory deterioration due to restraint stress. In ORT, celecoxib reversed memory impairment due to both alcohol and restraint stress.

Magnesium Increases the Protective Effect of Citicoline on Aluminum Chloride-induced Cognitive Impairment.

OBJECTIVE: Alzheimer's disease is a popular neurodegenerative disorder which is growing in the elderly people. Exposure to environmental pollutant like aluminum could trigger or accelerate its involved mechanisms like tau phosphorylation. The current study will evaluate the effect of alone or co-administration of Citicoline or/and magnesium on the aluminum chloride induced memory impairment. METHODS: Male albino mice were randomly divided into different groups (n = 7). Memory impairment was induced via orally administration of 300 mg/kg Aluminum Chloride for 28 days. Based on respective group, animals received 100, 250, 500 mg/kg of Citicoline or 50, 100, 150 mg/kg of Magnesium sulfate (MgSO4), intraperitoneally. In co-administration, 50 mg/kg of MgSO4 injected concomitantly with 100, 250, or 500 mg/kg of Citicoline. Rivastigmine (2 mg/kg intraperitoneally) was used as a positive control. Memory was evaluated using the Object Recognition Task (ORT) and Passive Avoidance Test (PAT). RESULTS: The studied doses of Citicoline or MgSO4 when administered individually showed significant increase in the discrimination index in ORT and latency time in the PAT compared to the Aluminium chloride (AlCl3) treated group. Concomitant injection of 50 mg/kg MgSO4 with the different doses of Citicoline strongly increased the above indices values in comparison to each alone. CONCLUSION: The findings show, individual administration of Citicoline or MgSO4 inverted the AlCl3-induced memory impairment in a dose independent manner. The addition of MgSO4 to the Citicoline showed a synergistic effect in the PAT and likely additive effect in the ORT.

Protective Effects of Citicoline and Benfotiamine Each Alone and in Combination on Streptozotocin-induced Memory Impairment in Mice.

OBJECTIVE: Diabetes mellitus is associated with cognitive disorders such as Alzheimer's disease. Studies have shown that citicoline and benfotiamine can improve memory and learning through different mechanism of actions. The aim of this study was to compare the individual effects of benfotiamine (100, 200, 300 mg/kg) and citicoline (50, 100, 250, 500 mg/kg, gavage) and their co-administration on memory impairments in diabetic mice. METHODS: Diabetes was induced by a single dose of streptozotocin (STZ, 140 mg/kg, intraperitoneal) and benfotiamine and/or citicoline were administered for three weeks. Memory was evaluated using the object recognition task (ORT) and passive avoidance test (PAT). RESULTS: Results from ORT shows that citicoline at 50, 100, 250, and 500 mg/kg and benfotiamine at 100, 200, and 300 mg/kg and their combination (benfotiamine at 100 mg/kg added to citicoline at 50, 100, and 250 mg/kg) are equally effective in reversing the memory loss induced by STZ (p < 0.001). PAT results demonstrate that citicoline at 100, 250, and 500 mg/kg and benfotiamine at above doses did not improve the latency time when administered separately, but benfotiamine at a fixed dose of 100 mg/kg in the presence of citicoline at 50, 100, and 250 mg/kg increased the latency time and improved memory significantly. CONCLUSION: In conclusion, in PAT, co-administration of benfotiamine and citicoline was more effective than either alone in improving memory. Regarding ORT, although benfotiamine added to citicoline improved memory notably, the difference between combination therapy and single-drug therapy was not considerable.

The effect of lead, restraint stress or their co-exposure on the movement disorders incidence in male mice.

Lead is known as an environmental contaminant with neurotoxic properties. In addition, people experience different types of chronic stress, especially in developing countries. It has been established that lead or stress causes structural and physiological damages to the neural pathway like dopaminergic connections. Nevertheless, the effect of lead and restraint stress on movement behaviors when are experienced together has not been studied yet. In this study, male albino mice were randomly divided into different groups (n = 6). Lead acetate was daily injected at 15 mg/kg intraperitoneally for 2, 4, or 6 weeks. Restraint stress (6 h in a day) was applied alone or in combination with lead acetate for 2, 4, or 6 weeks. The catalepsy, akinesia, and the balance of animals were measured by bar test, elevated beam device, and rotarod to evaluate the movement disorders. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a known neurotoxin causes movement disorders, was used as positive control group. The results showed that exposure to the lead or stress or their combination for 6 weeks caused catalepsy, akinesia, and imbalance in the animals, while exposure for 2 or 4 weeks didn't affect the movement items indices. The combination of lead and stress did not show any significant difference compared to the exposure to each of them individually. From the findings, Lead, stress, and their combination caused movement disorders in a time dependent manner. Short time exposure did not change movement behavior. The co-exposure to the lead and stress did not show additive or synergistic effects.

Solid Dispersion of Hesperetin Co-crystals Synergistically Attenuates Hepatic Toxicity of Carbon Tetrachloride Oxidative Stress in Rats.

BACKGROUND: Hesperetin (HSP) is a low water-soluble flavanone aglycone with low bioavailability. OBJECTIVES: This study aimed at enhancing the hepatoprotective effects of HSP by a combinatory technique based on solid dispersions of co-crystals of HSP. METHODS: Co-crystals were prepared using citric acid, tartaric acid, caffeine and isonicotinamide (INM) using two methods of solvent evaporation and co-grinding. The solid dispersion of co-crystals with different ratio of INM, PVP K30 and drug was prepared by the solvent evaporation method. The resulting material was characterized by DSC, XRD, FTIR and SEM, their saturated solubility and dissolution rate were compared to the pure drug. Finally, liver toxicity was induced in rats by carbon tetrachloride (CCl4) and mice were treated with different formulations of HSP. The liver function was tested by measurement of glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT), serum alkaline phosphatase (ALP) and bilirubin as well as histopathological tests. RESULTS: Although saturation solubility of HSP was enhanced about 5 times by co-crystals of HSP/INM (1:2), solid dispersions of the co-crystals of HSP obtained from PVP K30 and INM enhanced it up to 200 folds. Functional parameters of liver in rats pretreated with a solid dispersion of co-crystals of HSP were significantly lower than those with pure HSP and co-crystals of INM/HSP with 2:1 ratio. Furthermore, this formulations reduced liver damage effectively compared with the CCL4 group. CONCLUSION: Solid dispersion of HSP co-crystals synergistically attenuates hepatic toxicity of carbon tetrachloride oxidative stress in rats more effectively than its solid dispersions or co-crystals alone.

Comparative effects of chronic administrations of gabapentin, pregabalin and baclofen on rat memory using object recognition test.

Memory impairment is one of the greatest concerns when it comes to long-term CNS-affecting drug administration. Drugs like gabapentin, pregabalin and baclofen are administered in a long-term period in conditions such as epilepsy, neuropathic pain, spasticity associated with spinal cord injury or multiple sclerosis. Despite their wide spread use, few data are available on the effects of these drugs on cognitive functions, such as learning memory. In the present study, the effects of long-term administration of gabapentin, pregabalin and baclofen on memory were investigated in a comparative manner. Male Wistar rats received intraperitoneal (i.p.) injection of gabapentin (30 mg/kg), pregabalin (30 mg/kg), baclofen (3 mg/kg), combination of gabapentin/baclofen (30/3 mg/kg) and combination of pregabalin/baclofen (30/3 mg/kg) once a day for 3 weeks respective to their groups. After the end of treatments, rat memories were assessed using the object-recognition task. The discrimination and recognition indices (RI and DI) in the T2 trials were used as the memory indicating factors. The results showed that daily i.p. administrations of pregabalin but not gabapentin or baclofen significantly decreased DI and RI compared to saline group. In combination groups, either gabapentin or pregabalin impaired discrimination between new and familiar objects. Our findings suggested that pregabalin alone or in combination with baclofen significantly caused cognitive deficits.

Effect of acute and long term potassium bromide administration on spatial working memory in rat.

Potassium bromide (KBr), an old antiepileptic agent, is illegally used in pharmaceutical or food industries to improve the product appearance. KBr has been proven to influence several pathways which are important in memory formation. Therefore, the present study aimed to evaluate the effect of KBr on spatial working memory using object recognition task (ORT). Rats received a single dose of KBr (50, 100 or 150 mg/kg), per oral, in acute treatment. KBr long term effects were also studied in animals receiving 50 mg/kg/day of KBr for 28 consecutive days. At the end of treatments, animals underwent two trials of ORT, five min each. In the first trial (T1), animals encountered with two identical objects for exploration. After 1 h, the animals were exposed to a familiar and an unfamiliar object (T2). The exploration times for discrimination (D) and recognition (R) as well as the frequency of exploration for any objects were determined. Acute administration of 150 mg/kg of KBr significantly decreased the discrimination and recognition indices (RI and DI) (P < 0.01) compared to the control. However, lower doses failed to influence the animals' performance in the test. In addition, long term administration of KBr remarkably diminished the DI and RI and the frequency of exploration (P < 0.05). The results of this study indicate that acute doses of KBr as high as 150 mg/kg are required to hamper memory function in ORT. However, cognitive impairment occured with lower doses of KBr when the duration of treatment is extended.

Protective effect of vitamin C, vitamin B12 and omega-3 on lead-induced memory impairment in rat.

Lead belongs to the heavy metal group and is considered as an environmental contaminant. Acute or chronic contact to lead can change the physiological function of human organs. One of the most important disorders following the lead exposure is neurotoxicity. Lead neurotoxicity consists of the neurobehavioral disturbances like cognitive impairment. The aim of the current study is to evaluate the possible protective effect of vitamin C (Vit C), vitamin B12 (Vit B12), omega 3 (ω-3), or their combination on the lead-induced memory disorder. Adult wistar rats were orally administered Vit C (120 mg/kg/day) or Vit B12 (1 mg/kg/day) or ω-3 (1000 mg/kg/day) or their combination for 3 weeks in groups of 7 animals each. Then lead acetate (15 mg/kg/day) was injected intraperitoneally for one week to all pretreated animals. The control group received normal saline as a vehicle while the positive control for cognitive impairment received just lead acetate. At the end of treatments animal memories were evaluated in Object Recognition Task. The results showed, although 15 mg/kg lead acetate significantly declines the memory-evaluating parameters, pretreatment with Vit C, Vit B12, ω-3, or their combination considerably inverted the lead induced reduction in discrimination (d2) index (P < 0.001) and recognition (R) index (P < 0.001, P < 0.05, P < 0.05, and P < 0.001, respectively). Our findings indicate while lead acetate impairs spatial memory in rat, administration of Vit C, Vit B12, ω-3, or their combination prior to the lead exposure inhibits the lead induced cognitive loss. There was no remarkable difference in this effect between the used supplements.

Beneficial effect of Boswellia serrata gum resin on spatial learning and the dendritic tree of dentate gyrus granule cells in aged rats.

OBJECTIVE: The hippocampal formation, particularly the dentate gyrus (DG), shows age-related morphological changes that could cause memory decline. It is indicated that Boswellia resins attenuates memory deficits and the major component of Boswellia serrata (Bs) gum resin, beta boswellic acid increased neurite outgrowth and branching in hippocampal neurons. This study was designed to investigate the effect of Boswellia treatment on spatial learning performance and the morphology of dentate granule cells in aged rats. MATERIALS AND METHODS: Sixteen male Wistar rats (24 months old) were divided into experimental and control groups. Experimental group was intragastrically administered with the aqueous extract of Bs (100 mg/kg/d for 8 weeks) and control group received a similar volume of water. Spatial learning performance of rats was tested using Morris water maze task. At the end of experiment, the brain was removed and the right hippocampus was serially sectioned for morphometric analysis. The Cavalieri principle was employed to estimate the volume of the DG. A quantitative Golgi study was used to analyze the dendritic trees of dentate granule cells. RESULTS: Chronic treatment with Bs improved spatial learning capability during the three acquisition days. Comparisons also revealed that Bs-treated aged rat had greater DG with increased dendritic complexity in the dentate granule cells than control rats. Hippocampal granule cells of Bs-treated aged rats had more dendritic segments, larger arbors, more numerical branching density and more dendritic spines in comparison to control animals. CONCLUSION: This study provided a neuro-anatomical basis for memory improvement due to chronic treatment with Bs.

Acute and chronic tramadol administration impair spatial memory in rat.

Tramadol hydrochloride, a synthetic opioid, acts via a multiple mechanism of action. Tramadol can potentially change the behavioral phenomena. The present study evaluates the effect of tramadol after single or multiple dose/s on the spatial memory of rat using object recognition task (ORT). Tramadol, 20 mg/kg, was injected intraperitoneally (i.p) as a single dose or once a day for 21 successive days considered as acute or chronic treatment respectively. After treatment, animals underwent two trials in the ORT. In the first trial (T1), animals encountered with two identical objects for exploration in a five-minute period. After 1 h, in the T2 trial, the animals were exposed to a familiar and a nonfamiliar object. The exploration times and frequency of the exploration for any objects were recorded. The results showed that tramadol decreased the exploration times for the nonfamiliar object in the T2 trial when administered either as a single dose (P<0.001) or as the multiple dose (P<0.05) compared to the respective control groups. Both acute and chronic tramadol administration eliminated the different frequency of exploration between the familiar and nonfamiliar objects. Our findings revealed that tramadol impaired memory when administered acutely or chronically. Single dose administration of tramadol showed more destructive effect than multiple doses of tramadol on the memory. The observed data can be explained by the inhibitory effects of tramadol on the wide range of neurotransmitters and receptors including muscarinic, N-methyl D-aspartate, AMPA as well as some second messenger like cAMP and cGMP or its stimulatory effect on the opioid, gama amino butyric acid, dopamine or serotonin in the brain.

Effects of protein kinase A and G inhibitors on hippocampal cholinergic markers expressions in rolipram- and sildenafil-induced spatial memory improvement.

Although there are number of studies showing that phosphodiesterase (PDE) 4 and 5 inhibitors affect different kinds of memory, their effects on spatial memory consolidation in conjunction with the cholinergic activity in the hippocampus have not been studied before. In the present study firstly, rats were evaluated for the effects of different doses of the PDE4 inhibitor rolipram and the PDE5 inhibitor sildenafil on spatial memory consolidation in the water maze task. Rolipram or sildenafil was daily administered intraperitoneally 3 or 0 h after the last trial of training, respectively. Then in a separate related experiment the effect of the most efficient doses of rolipram or sildenafil accompanied by an intrahippocampally injected protein kinase A (PKA) or protein kinase G (PKG) inhibitor, respectively, was examined. Finally for determination of the hippocampal cholinergic activity the protein expression of hippocampal vesicular acetylcholine transporter (VAChT) and cholineacetyltransferase (ChAT) was measured. Rolipram at 0.03 mg/kg as well as sildenafil at 3 mg/kg increased spatial memory and their enhancing effect was completely blocked following inhibition of PKA and PKG, respectively. Furthermore, none of the treatments had a significant effect on the hippocampal ChAT and VAChT levels. Our data showed that rolipram and sildenafil enhanced spatial memory consolidation in an inverted U-shaped dose-response curve. This effect is dependent on the activity of cAMP/PKA- and cGMP/PKG-mediated pathways, respectively in the hippocampus. However, we did not find evidence for a chronic increase of cholinergic activity in the observed PDE inhibitor-induced memory improvement.

Interactive effects of a protein kinase AII inhibitor and testosterone on spatial learning in the Morris water maze.

Neurohormones such as testosterone (TE) are important in modulation of learning and memory. In the present study, we investigated the interactive effects of pre-training bilateral intra-hippocampal infusions of testosterone and H-89, a selective PKAII inhibitor, on spatial acquisition in the Morris water maze (MWM). Different doses of TE (20, 40 and 80 µg/side) and H-89 (5 and 10 µM/side) were administered 30 min before start of the training each day. Control animals received bilateral intra-hippocampal infusions of DMSO as vehicle for TE and H-89. Animals were trained for 4 days and each day included one block of four trials. The results of this study showed that bilateral infusion of TE (40 and 80 µg/side) or H-89 (10 µM/side) impaired spatial learning as indicated by significant increases in escape latency and traveled distance compared to the control group. Although pre-training bilateral infusions of a low concentration of either TE (20 µg/side) or H-89 (5 µM/side) into the CA1 region of the hippocampus did not affect learning capabilities, but the combination of the low doses of the drugs led to significant deficits in spatial acquisition. Overall, our data suggest that spatial acquisition was affected by PKAII inhibition or TE administration. Moreover, when co-administered, these drugs had a negative synergistic impact on acquisition.

The effect of prenatal exposure to restraint stress on hippocampal granule neurons of adult rat offspring.

OBJECTIVES: It is well known that prenatal stresses (PS) induce a variety of neurobiological and behavioral alterations, some of them involving the hippocampal formation. This study aimed to determine whether restraint stress influences the neuronal volume and number of granule cells in the hippocampus of adult rat offspring. MATERIALS AND METHODS: TEN WISTAR PREGNANT RATS WERE RANDOMLY DIVIDED: stressed and control groups. Pregnant dams in the stressed group were placed in a Plexiglas restraint tube for 1 hr daily from days 15-21 of gestation. Neuroendocrinological consequences of prenatal stress exposure were evaluated in the male offspring on postnatal day 60. The total numbers and the individual volume of granule cells in the hippocampus were also estimated with the optical fractionator and the rotator methods, respectively. RESULTS: Prenatally stressed rats exhibited prolonged elevation in plasma glucocorticoid levels following acute exposure to restraint stress. Data also indicated that there is a decrease in neuronal volume of hippocampal granule cells in prenatally stressed compared with their controls (625±64.1 µm(3) vs. 741±80.6 µm(3)). There was no significant difference in the total number of granule cells between prenatally stressed and control animals. CONCLUSION: The present study indicated that exposure of pregnant female during last week of pregnancy leads to a decline in neuronal size in hippocampus of adult male rats without neuronal loss. The present results may provide a basis for the understanding of the reported disturbances in behavior and learning of PS offspring.

Evaluation of systemic administration of Boswellia papyrifera extracts on spatial memory retention in male rats.

Time-dependent effects of ethanolic extract of Boswellia papyrifera, administered systemically, on spatial memory retention in the Morris water maze were investigated in male rats. A total extract of Boswellia papyrifera (300 mg/kg) was administered every eight hours to three groups of rats by gavage for 1, 2 and 4 weeks. In a separate set of experiments, three doses of a fraction of the extract, called the boswellic acids (100, 200 and 300 mg/kg) were administered by gavage to three groups of rats three times a day for 2 weeks. Following these applications, animals were trained for 4 days. Behavioral testing for evaluation of spatial memory retention was performed 48 h after completion of training. Boswellia papyrifera extracts and boswellic acids caused a significant reduction in escape latency and distance traveled but had no influence on swimming speed. These findings provide evidence that Boswellia papyrifera extracts affect spatial memory retention irrespective of the treatment period. In addition our data show that systemic administration of the boswellic acids fraction enhanced spatial memory retention in a dose-dependent manner. These improving effects may be due to some extent to the interactions of these products with inflammatory mediators, neurotransmitter signaling cascades or protein kinase pathways in the brain.

Effects of Selective iNOS Inhibitor on Spatial Memory in Recovered and Non-Recovered Ketamine Induced Anesthesia.

Nitric oxide (NO) is thought to be involved in spatial learning and memory in several brain areas such as hippocampus. This study examined the effects of post-training intrahippocampal microinjections of 1400W as a selective iNOS inhibitor on spatial memory, in anesthetized and non-anesthetized situations in rats. In the present work, 4-day training trials of animals were conducted. Spatial memory was tested 48 hours after the drug infusions. For microinjection of 1400W into CA1 region of the hippocampus in conscious animals, guide cannula was implanted into the CA1 area and 1400W was infused after recovery from surgical anesthesia. In anesthetized animals, 1400W was microinjected directly into CA1 region by Hamilton syringe during anesthesia. After completion of training, 1400W (10, 50 and 100 µM/side) were microinjected bilaterally (1 µL/side) and testing trials were performed 48 h after drug infusions in both groups of cannulated and non-cannulated rats. Significant reduction was observed in escape latency and traveled distance in animals that received 1400W (100 µM/side, *p < 0.05) via cannula after recovery in comparison with control group. Also, microinjection of 1400W (100 µM/side) in post recovery phase caused a significant (***p < 0.001) reduction in time and distance of finding the hidden platform in comparison with anesthetized situation. These findings suggest that 1400W has a significant improvement on spatial memory and memory enhancement induced by iNOS inhibitor can be affected by anesthesia in a period of time.

The quantitative evaluation of cholinergic markers in spatial memory improvement induced by nicotine-bucladesine combination in rats.

We previously showed that post-training intra-hippocampal infusion of nicotine-bucladesine combination enhanced spatial memory retention in the Morris water maze. Here we investigated the role of cholinergic markers in nicotine-bucladesine combination-induced memory improvement. We assessed the expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in CA1 region of the hippocampus and medial septal area (MSA) of the brain. Post-training bilateral infusion of a low concentration of either nicotine or bucladesine into the CA1 region of the hippocampus did not affect spatial memory significantly. Quantitative immunostaining analysis of optical density in CA1 regions and evaluation of immunopositive neurons in medial septal area of brain sections from all combination groups revealed a significant increase (P<0.001) in the ChAT and VAChT immunoreactivity. The maximum increase was observed with combination of 10-microM/side bucladesine and 0.5 microg/side nicotine and in a concentration dependent manner. Also, increase in the optical density and amount of ChAT and VAChT immunostaining correlated with the decrease in escape latency and traveled distance in rats treated with nicotine and low dose of bucladesine. Taken together, these results suggest that significant increases of ChAT and VAChT protein expressions in the CA1 region and medial septal area are the possible mechanisms of spatial memory improvement induced by nicotine-bucladesine combination.

Effects of Selective iNOS Inhibitor on Spatial Memory in Recovered and Non-recovered Ketamine Induced-anesthesia in Wistar Rats.

Nitric oxide (NO) is thought to be involved in spatial learning and memory in several brain areas such as hippocampus. This study examined the effects of post-training intrahippocampal microinjections of 1400W as a selective inducible nitric oxide synthase (iNOS) inhibitor on spatial memory, in both anesthetized and non-anesthetized situations in rats. In the present work, 4-day training trials of animals were conducted. Spatial memory was tested 48 h after the drug infusions. For microinjection of 1400W into CA1 region of the hippocampus in conscious animals, guide cannula was implanted into the CA1 area and 1400W was infused after recovery from surgical anesthesia. In anesthetized animals, 1400W was microinjected directly into CA1 region by Hamilton syringe during anesthesia. After completion of training, 1400W (10, 50 and 100 µM/side) were microinjected bilaterally (1 µL/side) and testing trials were performed 48 h after drug infusions in both groups of cannulated and non-cannulated rats. Significant reduction was observed in escape latency and traveled distance in animals that received 1400W (100 µM/side, * P < 0.05) via cannula after recovery in comparison with control group. Moreover, microinjection of 1400W (100 µM/side) in post recovery phase also caused a significant (*** P < 0.001) reduction in time and distance of finding the hidden platform in comparison with anesthetized situation. These results suggest that 1400W has a significant improvement on spatial memory, and memory enhancement induced by iNOS inhibitor can be affected by anesthesia in a period of time.

Protective effects of chronic lithium treatment against spatial memory retention deficits induced by the protein kinase AII inhibitor H-89 in rats.

We have previously shown that infusion of the PKAII inhibitor H-89 in the CA1 area of the hippocampus impaired spatial memory retention. There is some evidence suggesting the neuroprotective effects of chronic lithium administration including its ability to attenuate a deleterious effect of chronic stress on spatial memory in rats. In the present study, we investigated whether chronic administration of lithium can improve memory as well as influence the inhibitory effect of H-89 on spatial memory retention. Male albino rats were treated systemically with lithium (600 mg/l) for 4 weeks and then trained for 4 days in the Morris water maze. Testing the animals 48 h later showed a significant reduction in escape latency (p < 0.05) and travel distance (p < 0.05) compared to the controls. In separate experiments, the rats were similarly treated with lithium for 4 weeks, followed by similar training for 4 days and then immediately infused bilaterally with vehicle or 5 micromol/l H-89 into the CA1 region of the hippocampus. Animals were then tested 48 h after H-89 infusion in order to assess their spatial memory retention. The lithium treatment caused a significant reduction in escape latency (p < 0.001) and travel distance (p < 0.001) compared to H-89-treated animals. The data suggest that lithium treatment for 4 weeks improved spatial memory retention and that lithium pretreatment prevented or reversed the H-89-induced spatial memory deficits.