مهدی صادق

Epilepsy is one of the most common neurological disorders that affect social, economic, and biological aspects of human life. Thus, this study aimed to investigate the effect of Aqueous extract of Artemisia absinthium on PTZ-induced seizures in male rats.

 30 male rats have been chosen randomly and divided into 5 groups; including a control group, vehicle group, and three experimental groups. Treated rats received an aqueous extract of Artemisia absinthium via i.p. injection at doses of 50, 100, and 200 mg/kg before injection of pentylenetetrazole (PTZ). Thirty minutes after injection with different doses of the herb or distilled water (vehicle group), pentylenetetrazole (PTZ; 80mg/kg) was injected intraperitoneally. Animals were immediately transferred to a special cage and the seizure behaviors were recorded by a camera for 30 minutes. Then latency time of seizure onset, stage 5 seizure duration, and incidence and rate of mortality were measured in the groups. The data analysis was carried out via one-way ANOVA and Tukey post-hoc tests. Moreover, a difference of less than<0.05 was considered
significant.

Our results showed a significant increase in latency to reach stages 4 (P˂0.01) and 5 (P˂0.001)of tonic-clonic seizure at a dose of 100 mg/kg hyssop extract and decreased stage 5 duration (P˂0.05)  and rate of mortality.

Intraperitoneally injection of the aqueous extract of Artemisia absinthium has anticonvulsant effects on PTZ-induced seizure in a dose-response manner. Therefore, complementary research is recommended to identify some effective components of this plant on seizures.

Maternal folate supplementation during pregnancy is associated with reduced risk of several fetal neurodevelopmental disorders. However, it is not well known that excess folate intake from diet and supplements can impair neurodevelopment and behavior in offspring. Therefore, the aim of this study is to investigate the effect of chronic and high doses of folic acid before and during pregnancy in female rats on learning and spatial and avoidance memory in male and female offspring.

24 female Wistar rats received doses of 0.5, 1, and 2 mg folic acid by intraperitoneal injection two weeks before and during pregnancy. The control group received normal saline. Male and female offspring were divided into 8 groups. Learning behavior and spatial memory were measured by Morris blue maze test, avoidance memory by shuttle box test. The results showed that taking a dose of 2 mg folic acid before and during pregnancy causes spatial learning deficits in male offspring.

While spatial memory is unchanged compared to the control. This dose of folic acid also causes a disturbance in avoidance memory in both male and female offspring.

Our results suggest that high doses of folic acid supplements during early life (fetal) have the potential to impair neurological functions such as memory. Although the severity of this disorder can depend on the gender of the child.

Morphine as a strong analgesic compound is widely prescribed in clinic to control medium to severe pain, they are also may cause drug abuse. Recent studies have shown chronic morphine consumption and it could induce oxidative stress and cause cell damage. In this study, the effects of daily swimming exercise investigated on oxidative stress indices in the hippocampus and plasma of morphine dependent rats.

In this study, 48 adult male wistar rats were randomly divided to four groups. Experiments were done during January to March 2022 at Arak University of Medical Sciences. Morphine was self-administrated for 4 weeks, as dissolved (0.4 mg/ml) in the daily drinking water. Exercise training was included 15 minutes daily continuous swimming in a swimming pool. Swimming occurred during all days of morphine consumption. At the end, 6 rats were randomly selected from each group and withdrawal signs were evaluated by naloxone injection, to confirm morphine dependency. Then, hippocampus and plasma were collected from the 8 remaining rats of each group and were used for GSH, GSSG, MDA, irisin and BDNF assessment.

All rats in morphine consumed groups showed withdrawal signs in naloxone text, which means morphine dependency successfully were induced. However swimming exercise significantly reduced the consumption size of morphine. GSH was significantly decreased, while GSSG and MDA were significantly increased in the plasma and hippocampus of morphine groups in compare with control. Morphine consumption had no effect on plasma levels of irisin, while significantly decreased hippocampus level of BDNF. Daily swimming exercise in the morphine consumed group significantly repaired morphine effects on plasma and hippocampus levels of GSH, GSSG, MDA and hippocampus levels of BDNF.

Daily swimming exercise during the morphine consumption is able to repair at least some parts of the oxidative stress induced by morphine. This effect might help to reduce cellular and molecular damages raised by chronic morphine consumption.

Anticonvulsive effects of neurosteroids were shown in animal models. Endocannabinoids modulate neuronal excitability. In this study, we investigated the synergism of the simultaneous application of Palmitoylethanolamide (PEA) as an endocannabinoid and Ganaxolone as a neurosteroid, on tonic-clonic seizures induced by PTZ. 

Adult male Wistar rats were used. The tonic-colonic seizure was induced through a single injection of PTZ (80 mg/kg) and seizure stages were monitored for 30 minutes. Ganaxolone (10 mg/kg) and PEA (40 mg/kg) dissolved in DMSO were injected alone and simultaneously intra-peritoneal 15 minutes before the PTZ injection. Delay to the seizure stages, duration of the stages, and mortality due to seizures were measured.

PEA had no significant effect on seizure indices. Ganaxolone significantly increased delay to seizure stages 1-4 and reduced the duration of stage 5, also mortality of seizures was reduced in comparison with PTZ group from 50% to 16%.  Simultaneous injection of PEA and Ganaxolone significantly delayed seizure stages 1-5 in comparison with both PTZ and Ganaxolone groups and reduced the duration of stage 5. Also, mortality due to seizures was reduced in comparison with PTZ group from 50% to 0%.

PEA injection with Ganaxolone increased the anticonvulsive effects of Ganaxolone, and reduced mortality due to seizures.

Valproic acid derivatives are histone deacetylases (HDACs) inhibitors. HDACs are important in epigenetic processes. Some epigenetic modifications are inherited. This study aimed at investigating the intergenerational effects of pre-pregnancy chronic valproate consumption on offspring.

In this experimental study, twelve female Wistar rats were randomly divided into two groups of control and valproate. For 30 days, the control group received saline and the valproate group received sodium valproate (300 mg/kg) intraperitoneally (i.p.). After mating, pregnancy, and nursing, two males and two females pup were randomly selected from the mothers and placed in the following groups: 1) male offspring of the control group, 2) female offspring of the control group, 3) male offspring of the valproate group, and 4) female offspring of the valproate group. Future experiments were followed using these groups. Avoidance memory was assessed using the shuttle box. Offspring's hippocampus were extracted and used for MECP2, HDAC2, BDNF genes expression study by qRT-PCR.

No significant differences were detected in avoidance memory between male and female offspring of the mothers in valproate group and that of the controls (P>0.05). There were no significant differences in MECP2, HDAC2, and BDNF genes expression between male offspring of the mothers in control and valproate groups (P>0.05). But, expression levels of these genes significantly decreased in female offspring of valproate mothers compared with those of the female offspring of the controls (P<0.05).

Pre-pregnancy chronic valproate consumption did not affect avoidance memory in offspring. But, it seems to affect hippocampus gene expression sex-dependently.

Lipasin is a liver-derived secretory protein; i.e. associated with type 2 diabetes mellitus, obesity, and metabolic syndrome.  

The current research assessed the effect of resistance training on atherogenic and metabolic status and lipasin levels in obese rats.

 In this experimental study, 20 obese rats (8 weeks old, Mean±SD weight: 361±32 g) and 10 normal-weight rats (8 weeks old, Mean±SD weight: 248±13 g) randomly divided into three groups: obese control, obese trained, and control. The obese trained group received an 8-week exercise program for 3 days/week on a specific ladder with a carrying load of 30% of body weight, attached to their tails. The weight of the load was gradually increased during the training sessions, reaching 200% of the body weight of rats in the final week. There were three sets of 5 repetitions with a 3-min rest between each set of exercise sessions and 1 minute between repetitions. Forty-eight hours after the last training session, the blood samples were obtained and analyzed for metabolic status. The collected data were analyzed using analysis of variance (ANOVA), and statistical significance was set at P<0.05. 

Lipasin levels were higher in obese rats, than the controls (P=0.02). Atherogenic and metabolic status (TG, TC, LDL, glucose, insulin resistance) were improved in the exercise group, compared to the control group (P=0.05). Plasma lipasin levels were significantly decreased in the obese exercise group (P=0.05). 

 This study indicated that resistance training may be effective in improving metabolic status by decreasing lipasin plasma levels.

Peripheral and central nervous system neuropathy occur in chronic diabetes with uncontrolled hyperglycemia. Beneficial effects of sodium valproate have been demonstrated in neurodegenerative diseases. Sodium valproate has neuroprotective and regenerative effects via modifications in gene expression. In this study, we investigated effects of sodium valproate on the modifications in the hippocampal levels of NF-KB, AP-1, S100B and GFAP as a consequence of alloxan induced diabetes.
Material and This experimental study included 24 adult male C57B15/J mice. Diabetes was induced by injection of alloxan (150 mg/kg; i.p.). Sodium valproate was administrated (100 mg/kg; i.p) every 72 hours for two months. Fasting blood sugar levels were measured at the beginning and at the end of the experiment. Then animals were killed, their hippocampuses were extracted and prepared for measurement of biochemical factors by ELISA kits. Increased blood glucose levels due to alloxan induced diabetes were significantly reduced following sodium valproate administration (P<0.05). Also, chronic sodium valproate administration in diabetic animals significantly reduced elevated levels of hippocampal NF-KB, S100B and GFAP (P<0.05). It seems that sodium valproate can adjust diabetes induced modifications in the biochemical factors of the hippocampus which are indicators of cell damage, and maybe effective in prevention of diabetic neuropathy

Learning and memory defect occurs following chronic diabetes with uncontrolled blood glucose. Ginkgo leaf extract improves brain blood flow. Also it contains antioxidant components and has shown beneficial effects in neurological diseases. In this study we investigated the effects of Ginkgo leaf extract on spatial memory impairment and hippocampal neuronal loss caused by diabetes.
Material and This experimental study included 28 adult male Sparague-Dawley rats. The rats were made diabetic by injection of streptozotocin (STZ: 60 mg/kg). Ginkgo leaf extract (40 mg/kg) was administrated orally every day for two weeks and its effects on memory impairment and hippocampal tissue damage were investigated. Spatial memory was assessed in Morris water maze for four days. Then, the brains of the animals were extracted and after tissue staining hippocampal tissue damage were evaluated by neuronal count.
Latency to find the platform in water maze were significantly increased in STZ group compared to that in the control group (p Ginkgo leaf extract significantly improved spatial memory impairment and hippocampal neuronal loss, induced by diabetes.

Salicylates and opioids are widely used in chronic pain relief. Chronic use of these drugs reorganizes synaptic function, especially experience-dependent plasticity in brain regions. Therefore, in this study the effects of chronic administration of salicylate and morphine on synaptic plasticity were investigated.
in this review, Elsevier, Science Direct, PubMed and Google Scholar databases were searched for the following keywords: salicylate, morphine, drug tolerance, and synaptic plasticity. At the end, 62 of the obtained reports were included in the study.
In addition to induction of tolerance to anti-nociceptive effect and cross-tolerance, chronic salicylate administration as like as morphine has long-lasting effects on hippocampal neuronal networks which are manifested as excitability of neurons and ability of activity and experience-dependent plasticity. Some of these effects can be documented in the hippocampus-related functions such as spatial learning and memory.
Considering the effects of salicylate and morphine on the nervous system and synaptic transmission, the effects of these drugs on the processing of input data and as a result on cognitive functioning would not be unlikely, thus necessitating further behavioral and electrophysiological studies.

According to the increasing opioids abuse between women and pathophysiological effects of chronic exposure of opioids on mothers which might indirectly affect their offspring, herein, consequences of chronic morphine consumption and its withdrawal before the gestation was investigated on spatial memory, avoidance memory and vulnerability to morphine intake in offspring of first generation.
Twelve female Wistar rats were randomly divided into two groups. Morphine mothers group received morphine solution (0.4 mg/ml) for two months. Control mothers group received tab water. One month after stopping morphine consumption, mating was occurred. After the parturition, offspring was divided in separated male and female groups and was used as the target groups of the study. Spatial memory through Water Maze, avoidance memory through Shuttle Box and vulnerability to morphine intake through voluntary consumption of morphine solution were investigated.
Mean of morphine solution consumption in male and female offspring of morphine mothers was significantly higher in compare to male and female offspring of control mothers (P Our study revealedchronic morphine consumption before the gestation causesdamage of spatial memory in male offspring and also increases vulnerability to opiate intake of male and female offspring.

In spite of various and effective anti seizure drugs available, 30% of epileptic patients are not adequately treated with current medications. Based on the effectiveness of phytocannabinoids on epileptic and seizure models, in this study the effects of 2-achidonoylglycerol (2-AG) injection, as an important endocannabinoid, on tonic-clonic seizures induced by pentylenetetrazol (PTZ) was examined.
The study was performed on male wistar rats (180-200 g). Tonic-clonic seizures were induced through a single intra-peritoneal injection of PTZ (80 mg/Kg) and then seizure behavior was monitored for 30 minutes. The intra-peritoneal injection of 2-AG (1 mg/Kg) in dimethyl solfoxide (DMSO) was performed 15 minutes before the PTZ injection. In the sham group an equivalent volume of DMSO was injected 15 minutes before PTZ. Data on the delay of seizure stage occurrence, duration of the stages, number of occurrences for each stage and mortality rate due to tonic-clonic seizures were collected for analysis.
PTZ injection in association with DMSO significantly increased the delay for seizure stages 1 and 2, in comparison with just a PTZ injection (P It seems 2-AG injection could be effective in reducing seizure parameters in seizures induced by PTZ.

Melatonin regulates the sleep-wake cycle and is protected against oxidants. Vitamin E has antioxidant effect. The aim of this study was to investigate effect of melatonin and/or vitamin E on the EEG, sleep quality and quality of life of female nurses working in hospitals in Arak.
60 female nurses were randomly selected from hospitals in the Arak city. Participants divided into three groups (melatonin3 mg/day, vitamin E 200 IU/day and melatonin and vitamin E groups) and a control group. Before and two months after the baseline, PSQTI and the quality of life of 26 questions questionnaire were completed and EEG was recorded. Finally, the findings for both groups before and after the intervention were compared with each other.
The average of sleep quality showed an improvement in groups receiving melatonin and melatonin븫媚 E (p>0.05). While data of life quality did not show any significant change between groups. In EEG activity, α waves in the range of 8-10 Hz showed maximum increase in melatonin group and minimum increase in vitamin E group. Also, α wave in the range of 10-12 Hz revealed the most decrease in the melatonin group.
It seems simultaneous administration of melatonin and vitamin E is able to improve sleep quality. In addition, melatonin could improve alpha-waves of brain activity.

In recent years, numerous attempts were done to find new treatment methods for patients with drug-resistant epilepsy. Anandamide (Anandamides; AEA) and di-Arachidonoylglycerol (2-Arachidonoylglycerol; 2-AG) are two major ligands of endocannabinoid system can be produced or deleted by a certain enzymatic pathway. Given the frequency and significance of these endocannabinoid ligands, it seems that endocannabinoid system in the brain can be changed with pharmacologically manipulating in the pathway of these two main ligands. Therefore, the aim of this study was to evaluate the effect of enzymatic elimination of endocannabinoids inhibitors on tonic-clonic seizure caused by PTZ.
In this exprimental study 35 Adult male wistar rats were used in 4 groups. Tonic-colonic seizure was induced through single intra-peritoneal injection of PTZ (80 mg/Kg). Latency and duration of each five behavioral seizure stages were monitored for 30 minutes. To inhibit Anandamides elimination, URB and LY (URB: 1 mg/kg, LY: 2.5 mg/kg, i.p), to inhibit 2-2-Arachidonoylglycerol degradation WWL and JJKK (JJKK: 1 mg/kg, WWL: 5 mg/kg, i.p), were used, all dissolved in DMSO and injected 15 minutes before PTZ injection. In sham group, PTZ was injected after DMSO.Time and duration of all five behavioral stages of seizure were recorded for 30 minutes.
FINDINGS: Delay to stages 4 and 5 in DMSO㴶 group were 206 and 209, respectivly. While in JJKK奢︌쒎 group delay to stages 4 and 5 were 630힟 and 726�, respectivly, which reveald significant increase (p Contemporary using both WWL and JJKK as inhibitors of 2-Arachidonoylglycerol elimination effectivly reduced tonic- clonic seizure.

In this study, relation between spatial learning ability in Morris Water Maze (MWM) and rotational-bias of male and female rats has been studied. Spatial learning ability of 54 male and female rats was evaluated in MWM and the relationship between spatial learning ability and rotational-bias of animal in MWM has been considered. Spatial learning ability in left side rotating male rats was better than those rotating to the right. However, in females, spatial learning ability in right rotating and retrieval of memory in left rotating animals were better. Comparing side-bias in male and female rats showed that spatial learning ability in right rotating and retrieval of memory in left rotating female rats were better than males. Our results showed that spatial learning ability in MWM could be anticipated by knowing the rotational bias of male or female rats in MWM. Considering this variable could help us to better explain the gender differences in the Morris water maze.

In current study the consequence of chronic exposure of male and female rats to mobile-phone irradiation (900 MHz) and electromagnetic field (50 Hz) during the embryonic period on plasma and brain tissue total antioxidant capacity (TAC) and malondialdehyde (MDA) level were investigated.
Material and After fertilization, female rats (n=9) were randomly divided into three groups: Control, Mobile phone -exposure and Exposure to 50 Hz electromagnetic field using a solenoid (LF). In LF group, female rats were placed daily inside a solenoid (50 Hz and 1.5 mT) for 30 minutes until giving birth. In Mobile-phone group, female rats were kept in their home cage while mobile-phone was placed in standby mode under the cage and turned on to calling mode 30 minutes each day until giving birth. After parturition and milk feeding, female and male pups were divided into 6 separated groups to measure TAC and MDA taken from plasma and brain.
In Control group the values of TAC and MDA for plasma and brain tissue showed no significant differences between the male and females rats. In addition, plasma TAC for Mobile-phone and LF groups showed no difference compared to Control. No significant difference was seen for plasma and brain MDA between the Mobile-phone and LF groups.
Our results revealed that chronic exposure to electromagnetic field during the embryonic period have no significant effect on brain and plasma TAC and MDA level.

Oxidative stress and severe neuro-excitation have significant effects on pathogenesis of Parkinson’s disease and agents with antioxidant property can potentially prevent these effects. Herein we examined potential protective effects of melatonin as an antioxidant agent and memantine as an uncompetitive receptor of NMDA, on a model of Parkinson’s disease induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Male mice were divided into 8 groups with 7 mice in each group: saline, ethanol, melatonin, memantin, MPTP, melatonin+MPTP, memantin+ MPTP, melatonin+ memantin+ MPTP. All of agents were injected intraperitoneally once a day for 14 days before beam traversal test. Dopaminergic neurons of the Substantia Nigra Pars compacta (SNPC) were determined by immunohistochemical and were counted. Melatonin improved notably movement dysfunction resulted of MPTP such as the number of errors, paces and the time of movement during behavioral test and also the counting of neurons of Substantia Nigra Pars Compacta. Memantin had a synergic effect on the most of improvements. However, the level of improvement and retrieval of signs was not as in saline and ethanol groups. Melatonin especially together with memantine is able to prevent some of the MPTP-induced dysfunctions. However, the protective effects were not enogh, probably because of the amount of dose and the time of injection.

Adenosine has been considered as a fine-tuner of the neurotransmitters in the nerve system. Adaptive changes in the brain adenosine system occur in some patho-physiological situations such as chronic exposure to morphine. In this study, the adaptive changes in the adenosine deaminase activity as a key enzyme in the adenosine metabolism that converts adenosine to inosine and ammonia, irreversibly, due to morphine dependence and tolerance to anti-nociceptive effects of sodium-salicylate were investigated. Morphine dependence was induced by morphine administration in tap water (0.4mg/ml for 24 days). Tolerance to sodium-salicylate was induced by 6 i.p. injection (1 injection/day) of sodium-salicylate. Tolerance to antinociceptive effects of sodium-salicylate was measured by tail flick (TF) and hot plate (HP) tests. Right hippocampus was dissected, homogenized at phosphate buffer, centrifuged and then the supernatant fraction was isolated. Protein content of the samples was measured by the Bradford method. Hippocampus adenosine deaminase activity was measured by a calorimetric method of enzyme assay which is based on the direct measurement of the produced ammonia from excessive adenosine degradation by adenosine deaminase. Daily injection of Sodium-salicylate produced antinociception in early days by latency increase rather than saline injection (P<0.0001) but in the following days this antinociceptive effect progressively decreased so at the day 5 and 6 following injection it was similar to saline (P>0.05). Injection of morphine (5mg/Kg) at the day 7 showed more increase in the latency of saline injected rather than sadium-salicylate injected (P<0.001). Adenosine deaminase activity was significantly higher in sucrose administrated rather than chronic morhine administrated (P<0.05) and in saline injected rather than sodium-salicylate injected (P<0.05). Single injection of sodium-salicylate and its control shows the same activity. There was no significant difference in enzyme activity of morphine dependent with sadium-salicylate tolerance (P>0.05). This decline in the adenosine deaminase activity may be related with adaptation in brain adenosine system subsequent of dependent to morphine or tolerance to sodium-salicylate.

The use of low-frequency electrical stimulation (LFS) as a therapy for epilepsy is currently being studied in experimental animals and patients with epilepsy. In the present study, we investigated the role of serine/threonine protein phosphatases in the inhibitory effects of LFS on perforant path kindling acquisition. Sixty four male Wistar rats were stimulated by perforant path stimulation in a rapid kindling manner (6 stimulations per day). The LFS (1 Hz) was applied immediately after termination of each kindling stimulation. The FK506 (1µM; i.c.v.), a serine/threonine protein phosphatase PP2B inhibitor and okadaic acid (1µM;i.c.v.), a serine/threonine protein phosphatases PP1/2A inhibitor, were daily microinjected into the left ventricle 10 min before starting the stimulation protocol. A two-way ANOVA was done to compare the seizure parameters of different groups. The effect of LFS on behavioral seizure scores was analyzed using the nonparametric Kruskal–Wallis and Mann–Whitney U tests. P value less than 0.05 was considered as the level of significance. Appling LFS immediately after kindling stimulation significantly retarded the kindling acquisition and delayed the expression of different kindled seizure stages. In addition, LFS significantly reduced the increment of daily after-discharge duration during kindling development. (P<0.001) Microinjection of neither FK506 nor okadaic acid had significant effect on the antiepileptogenic effect of LFS on kindling parameters. Our findings showed that activation of PP1/2A and PP2B, which play a critical role in LFS, induced down-regulation of synaptic strength, had no role in mediating the inhibitory effects of LFS on perforant path kindled seizures.

Following the seizure there is an inhibitory period named “post-ictal depression period” which has a depressing effect on the following seizure. In this study, the role of GABAA receptors on post-ictal depression period was investigated in amygdala kindling model of epilepsy in rat. Animals were kindled by electrical stimulation of amygdala. Then, they were divided into four groups. Different groups of kindled animals were received a second stimulation at 10, 30, 60 and 90 min after the first stimulation and the percentage of suppression of seizure parameters after the second stimulation was calculated. In another four groups, bicucullin, a selective GABAA receptor antagonist (100 nM), was intra-cerebroventricularly microinjected 10 min before the second stimulation and its effect on the percentage of suppression induced by the first stimulation was investigated. Six animals were used in each group. When the second stimulation was applied at 10 and 30 min after the first stimulation a significant reduction was observed in the seizure severity and seizure parameters were depressed after the second stimulation. Bicucullin microinjection significantly decreased the percentage of depression in seizure parameters following the second stimulation compared to the animals received the solvent alone (P<0.05). This decrease was significant when the second stimulation was applied at 10 and 30 min after the first stimulation. Obtained results showed that activity of GABAA receptors by endogenous GABA is one of the mechanisms involved in post-ictal depressing period. However, the blocking of these receptors could not completely prevent this period. Thus, other factors have also role in its induction