Boosting decision-making in rat models of early-life adversity with environmental enrichment and intranasal oxytocin.

Impaired decision-making constitutes a fundamental issue in numerous psychiatric disorders. Extensive research has established that early life adversity (ELA) increases vulnerability to psychiatric disorders later in life. ELA in human neonates is associated with changes in cognitive, emotional, as well as reward-related processing. Maternal separation (MS) is an established animal model of ELA and has been shown to be associated with decision-making deficits. On the other hand, enriched environment (EE) and intranasal oxytocin (OT) administration have been demonstrated to have beneficial effects on decision-making in humans or animals. Given these considerations, our investigation sought to explore the impact of brief exposure to EE and intranasal OT administration on the decision-making abilities of adolescent rats that had experienced MS during infancy. The experimental protocol involved subjecting rat pups to the MS regimen for 180 min per day from postnatal day (PND) 1 to PND 21. Then, from PND 22 to PND 34, the rats were exposed to EE and/or received intranasal OT (2 µg/µl) for seven days. The assessment of decision-making abilities, using a rat gambling task (RGT), commenced during adolescence. Our findings revealed that MS led to impaired decision-making and a decreased percentage of advantageous choices. However, exposure to brief EE or intranasal OT administration mitigated the deficits induced by MS and improved the decision-making skills of maternally-separated rats. Furthermore, combination of these treatments did not yield additional benefits. These results suggest that EE and OT may hold promise as therapeutic interventions to enhance certain aspects of cognitive performance.

Transmission of behavioral and cognitive impairments across generations in rats subjected to prenatal valproic acid exposure.

BACKGROUND: Autism spectrum disorder (ASD) represents an inheritable neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Numerous studies have underscored the significant roles played by genetic and environmental factors in the etiology of ASD, and these factors are known to perpetuate behavioral impairments across generations. OBJECTIVES: The primary objective of this study was to assess the behavioral and cognitive attributes in the second filial (F2) generation of male and female rats, with a particular focus on those whose parents had been exposed to valproic acid (VPA) during embryonic development. METHODS: In this study, a cohort of 32 male and 32 female rats from the second filial (F2) generation, referred to as Mother.ASD, Father.ASD, or Both.ASD, was examined. These designations indicate whether the mother, father, or both parents had experienced embryonic exposure to valproic acid (600 mg/kg, i.p.). During adolescence, the F2 pups underwent behavioral and cognitive assessments, including open field testing, marble burying, social interaction evaluations, and Morris water maze tasks. RESULTS: Our data revealed that while both the Mother.ASD and Father.ASD groups, regardless of sex, exhibited elevated anxiety-like behavior in the open field test. Only the Mother.ASD group displayed repetitive behaviors and deficits in social memory. Additionally, spatial memory impairments were observed in both sexes. These findings highlight the transmission of autistic-like behaviors in the offspring of Mother.ASD rats from both sexes. Nevertheless, future research endeavors should be more targeted in identifying the specific genes responsible for this transmission. CONCLUSION: In summary, our findings underscore the transmission of autistic-like behaviors, including anxiety-like behavior, repetitive actions, impairments in social interactions, and deficits in memory, to the offspring of the Mother.ASD group, irrespective of their sex.

Effects of music on cognitive behavioral impairments in both sex of adult rats exposed prenatally to valproic acid.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive behaviors and interests. In previous studies, music has been identified as an intervention therapy for children with ASD. OBJECTIVES: The present study evaluated the effects of music on cognitive behavioral impairments in both sexes of adult rats exposed prenatally to Valproic acid. METHODS: For induction of autism, pregnant female rats were pretreated with either saline or VPA (600 mg/kg.i.p.) at gestational day (GD) 12.5. Male and female offspring were divided into Saline.Non-Music, VPA.Non-Music, Saline.Music, and VPA.Music groups. The adult rats in the music groups were exposed to Mozart's piano sonata K.448 for 30 days (4 h/day), from postnatal day (PND) 60 to 90. Social interaction and Morris water maze (MWM) tasks were tested at PND 90. RESULTS: Our results revealed that prenatal exposure to VPA decreased sociability and social memory performance in both sexes of adult rats. Moreover, prenatal exposure to VPA created learning and memory impairments in both sexes of adult rats in the MWM task. Music intervention improved sociability in both sexes of VPA-exposed rats and social memory in both sexes of VPA-exposed rats, especially in females. Furthermore, our results revealed that music ameliorated learning impairments in VPA-exposed female rats in the MWM task. In addition, music improved spatial memory impairments in VPA-exposed rats of both sexes, especially in females, which needs more investigation in molecular and histological fields in future studies. CONCLUSION: Music intervention improved sociability and social memory in adult VPA-exposed rats, especially in female animals. Furthermore, music improved memory impairments in VPA-exposed rats of both sexes. It seems that music had a better influence on female rats. However, future studies need more investigations in molecular and histological fields.

Music alleviates cognitive impairments in an animal model of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including impairment in social communication and restrictive and repetitive behaviors and interests. Music has emerged in the past decade as an intervention therapy for children with ASD. The aim of the present study was to evaluate the effects of music on cognition impairments in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism on embryonic day 12.5 (E12.5) (600 mg/kg). Male and female pups were sub divided into four main groups (Saline.Non-music, VPA.Non-music, Saline.Music, and VPA.Music). The rats in the music groups were exposed to Mozart's piano sonata K.448 for 30 days (4 h/day), from postnatal day (PND) 21 to 50. Autistic-like behaviors were tested using a social interaction, the Morris water maze (MWM), and a passive avoidance tasks at the end of the PND 50. Our results demonstrated that VPA-exposed rat pups had significantly lower sociability and social memory performance compared with the saline-exposed rats in both sexes. VPA-exposed rat pups exhibited learning and memory impairments in the MWM and passive avoidance tasks. Our results demonstrated that music improved sociability in VPA-exposed rats, especially in males. Furthermore, our findings revealed that music improved learning impairments in VPA-exposed male rats in MWM task. In addition, music improved spatial memory impairments in VPA-exposed rats of both sexes. We also found that music improved passive avoidance memory impairments in VPA-exposed rats of both sexes, especially in females. More investigation in future studies are needed.

Chronic morphine exposure and maternal separation induce impairments in cognition and locomotor activity of male adolescent rats.

Maternal morphine exposure reduces motivation for basic cognitive tasks, followed by executive function deficits in attention and accuracy. It also induces depression-like behaviors and has negative consequences for learning and memory in offspring. Interaction between mothers and pups has a crucial effect on the mammal's development. Maternal separation (MS) can originate behavioral and neuropsychiatric abnormalities later in life. It seems that adolescents are more susceptible to the effects of early-life stress; Therefore, this study aimed to evaluate the effects of chronic morphine consumption (21 days before and after mating and gestation) and MS (180 min/day from postnatal day [PND] 1-21) on the cognitive and behavioral performance of male offspring in mid-adolescence. Six groups, including control, MS, V (vehicle), morphine, V+MS, and morphine+MS, were tested for open field (OF), novel object recognition (NOR), and the Morris water maze (MWM). The results of the OF test showed that MS increased locomotor activity and movement velocity. Inner and outer zone durations did not differ among groups. The body stretching of the morphine+MS rats was significantly more than the MS rats. Moreover, the MS and morphine+MS groups showed significantly less sniffing behavior in the OF test. The MS group showed deficits in spatial learning in the MWM test, but recognition memory in the NOR and spatial memory in the MWM tests were not significantly different among groups. We concluded that MS could induce impairments in spatial learning and locomotor activity that could be worsened by maternal morphine exposure in adolescent male rats.

Characterization of prevalent tyrosine kinase inhibitors and their challenges in glioblastoma treatment.

Glioblastoma multiforme (GBM) is a highly aggressive malignant primary tumor in the central nervous system. Despite extensive efforts in radiotherapy, chemotherapy, and neurosurgery, there remains an inadequate level of improvement in treatment outcomes. The development of large-scale genomic and proteomic analysis suggests that GBMs are characterized by transcriptional heterogeneity, which is responsible for therapy resistance. Hence, knowledge about the genetic and epigenetic heterogeneity of GBM is crucial for developing effective treatments for this aggressive form of brain cancer. Tyrosine kinases (TKs) can act as signal transducers, regulate important cellular processes like differentiation, proliferation, apoptosis and metabolism. Therefore, TK inhibitors (TKIs) have been developed to specifically target these kinases. TKIs are categorized into allosteric and non-allosteric inhibitors. Irreversible inhibitors form covalent bonds, which can lead to longer-lasting effects. However, this can also increase the risk of off-target effects and toxicity. The development of TKIs as therapeutics through computer-aided drug design (CADD) and bioinformatic techniques enhance the potential to improve patients' survival rates. Therefore, the continued exploration of TKIs as drug targets is expected to lead to even more effective and specific therapeutics in the future.

Environmental enrichment and intranasal oxytocin administration reverse maternal separation-induced impairments of prosocial choice behavior.

Adverse early life experiences influence behavioral and physiological functions and increase vulnerability to neuropsychiatric disorders. Maternal separation (MS) is an established animal model that reproduces the features of chronic stress or adverse experiences during early life. Previous studies have been shown that MS may lead to impairments of social behaviors. Here, we investigated the effects of MS on mutual reward preferences in a double T-maze prosocial choice task. Since enriched environment (EE) and intranasal oxytocin (OT) administration have beneficial effects on cognition and social behaviors, in the present study we tested whether these treatments, alone or in combination, would affect prosocial behavior of rats which underwent MS during infancy. Rat pups underwent MS paradigm for 180 min/day from postnatal day (PND) 1-21. From PND 22-34, rats were exposed to an EE and/or received intranasal OT (2 µg/µl, 7 days). Hence, the 8 groups consisted of control (CTRL), MS, CTRL+EE, CTRL+OT and the saline groups. Assessment of prosocial choice behavior was started in adolescence. MS impaired prosocial choice behavior and reduced mutual reward preferences. Getting exposed to EE and intranasal OT administration could overcome MS-induced deficits and promoted mutual reward preferences of MS rats. Combination of short-term EE and OT strengthened prosocial behavior. Obtained results showed that EE and OT may be considered as profitable therapeutic approaches for promoting some aspects of social behavior.

Choline chloride modulates learning, memory, and synaptic plasticity impairments in maternally separated adolescent male rats.

Maternal separation (MS) is a model to induce permanent alternations in the central nervous system (CNS) and is associated with increased levels of anxiety and cognitive deficiencies. Since methyl donor choline (Ch) has been shown to play a significant role in learning and memory and enhance synaptic plasticity, the authors hypothesized that Ch may attenuate MS-induced impairments in synaptic plasticity and cognitive performance. Rat pups underwent an MS protocol for 180 min/day from postnatal day (PND) 1 to 21. Ch was administered subcutaneously (100 mg/kg, 21 days) to the choline chloride and MS + choline chloride groups from PND 29 to 49. Anxiety-like behaviour, recognition memory, and spatial and passive avoidance learning and memory were measured in the adolescent rats. In addition, evoked field excitatory postsynaptic potentials (fEPSP) were recorded from the CA1 region of the hippocampus. MS induced higher anxiety-like behaviour in the animals. It also impaired learning and memory. However, MS had no effect on locomotor activity. Subcutaneous administration of Ch attenuated MS-induced cognitive deficits and enhanced the learning and memory of MS rats. Ch also decreased anxiety-like behaviour in the open-field test. The present results showed that long-term potentiation (LTP) was induced in all groups except MS and MS + saline animals. However, Ch injection induced LTP and had maintenance in MS + choline chloride, but it was not statistically significant compared with the MS group. In summary, the present findings indicate that MS can interfere with normal animal's cognition and subcutaneous of Ch may be considered an appropriate therapeutic strategy for promoting cognitive dysfunctions in MS animals.

Effects of short environmental enrichment on early-life adversity induced cognitive alternations in adolescent rats.

Early-life experiences, including parental care, affect cognitive performance later in life. Being exposed to early-life maternal separation (MS) increases susceptibility to stress-related psychopathology. Previous studies suggest that MS could induce learning and memory impairments. Since enriched environment (EE) provides more opportunities for exploration and social interaction, in the present study we evaluated the effects of a short EE paradigm with a duration of 13 days on cognitive abilities of maternally separated rats (MS; 180 min/day, postnatal day (PND) 1-21) during adolescence in four experimental groups: Control, Control+EE, MS, and MS+EE. Plasma corticosterone (CORT) and brain-derived neurotrophic factor (BDNF) levels were also measured in experimental animals. We also studied the induction of long-term potentiation (LTP) in the slices of hippocampal CA1 area. The behavioral and electrophysiological assessments were started at PND 35. MS caused higher basal CORT levels in plasma and impaired spatial learning, memory, and social interaction. LTP induction was also impaired in MS rats and plasma BDNF levels were reduced in these animals. MS also induced more anxiety-like behavior. Short EE reduced plasma CORT levels had the potential to improve locomotor activity and anxiety-like behavior in MS+EE rats and reversed MS-induced impairments of spatial learning, memory, and social behavior. LTP induction and plasma BDNF levels were also enhanced in MS+EE rats. We concluded that short EE might be considered as a therapeutic strategy for promoting cognition.

Depresssion, anxiety and other cognitive consequences of social isolation: Drug and non-drug treatments.

OBJECTIVE: During the COVID-19 pandemic, quarantine and staying at home is advised. The social relationship between people has become deficient, and human social isolation (SI) has become the consequence of this situation. It was shown that SI has made changes in hippocampal neuroplasticity, which will lead to poor cognitive function and behavioural abnormalities. There is a connection between SI, learning, and memory impairments. In addition, anxiety-like behaviour and increased aggressive mood in long-term isolation have been revealed during the COVID-19 outbreak. METHODS: Term searches was done in Google Scholar, Scopus, ScienceDirect, Web of Science and PubMed databases as well as hand searching in key resource journals from 1979 to 2020. RESULTS: Studies have shown that some drug administrations may positively affect or even prevent social isolation consequences in animal models. These drug treatments have included opioid drugs, anti-depressants, Antioxidants, and herbal medications. In addition to drug interventions, there are non-drug treatments that include an enriched environment, regular exercise, and music. CONCLUSION: This manuscript aims to review improved cognitive impairments induced by SI during COVID-19.

Resveratrol Attenuates Learning, Memory, and Social Interaction Impairments in Rats Exposed to Arsenic.

Arsenic (As) toxicity has deleterious effects on human health causing disorder in the brain. The aim of this study was to investigate the possible neuroprotective effect of resveratrol (RSV) on arsenic-induced neurotoxicity in rats. Neurotoxicity in rats was developed by treating As 10 mg/kg/day for 21 days orally. Animals were put into seven groups: control, vehicle, As, As+RSV10, As+RSV20 mg/kg, RSV10, and RSV20 mg/kg. Behavioral assessments such as the social interaction test, novel object recognition test, elevated plus maze, open field, the Morris water maze, in addition to assessment of biomarkers such as ferric reducing ability of plasma assay, glutathione assay, and malondialdehyde assay, were used to evaluate the effects of RSV on cognitive impairment and molecular changes induced by As. The results showed that cognitive performance impaired in As rats. RSV20 mg/kg significantly could ameliorate behavioral changes like spatial learning in days 3 and 4 (p < 0.05), recognition learning and memory (p < 0.01), disabilities in motor coordination and stress (p < 0.05), increased anxiety (p < 0.05), and social interaction deficit (sociability (p < 0.001) and social memory (p < 0.05)). RSV20 mg/kg also attenuated molecular modifications like decreased antioxidant power (p < 0.001), reduced glutathione content (p < 0.05), and increased malondialdehyde level (p < 0.05) induced by As. In addition to oxidative stress assessments, RSV10 mg/kg could significantly increase FRAP (p < 0.01) and GSH (p < 0.05); however, MDA was not significantly increased. Our current behavioral findings suggest that RSV has neuroprotective effects against AS toxicity.

Maternal separation impairs mother's cognition 1 month beyond the separation.

OBJECTIVE: Separation of pups from their dam during the infancy not only has detrimental effects on the pups' brain but also affects dams' behavior. Postpartum stress may affect mothers' cognitive functions. In the present study, by using a 180-min day-1 maternal separation (MS) paradigm, we assessed anxiety-like behavior and locomotor activity of rat dams which experienced separation from postnatal day (PND) 1 until weaning. We tried for the first time to clarify whether such separation impairs dam's performance in the Morris water maze. METHOD: We assessed dams' behavior at three time points: 24 h, 1 week, and 1 month after weaning. Therefore, the six groups consisted of control (CTRL) 24 h, 1 week, and 1 month and MS 24 h, 1 week, and 1 month, which was allocated in this study. RESULTS: Our results revealed that although MS-24 h and MS-1 week groups had intact locomotor activity, MS-1 month group showed less locomotor activity in the open field. Moreover, MS-induced anxiety-like behavior was more pronounced in MS-1 week and MS-1 month dams. Spatial learning and memory was also impaired only in MS-1 month dams. CONCLUSION: We can conclude that MS induces cognitive impairments in dam that may appear not immediately after the separation but a few weeks after such stressful event.

Intranasal oxytocin administration facilitates the induction of long-term potentiation and promotes cognitive performance of maternally separated rats.

Maternal separation (MS) is known to induce permanent changes in the central nervous system and is associated with increased levels of anxiety and cognitive impairments. The neuropeptide oxytocin (OT) has been implicated in a broad spectrum of social and nonsocial and behaviors. Since it plays a significant role in learning and memory and enhances synaptic plasticity, we hypothesized that OT may affect MS-induced changes in synaptic plasticity and cognitive performance. Rat pups underwent MS protocol for 180 min/day from postnatal day (PND) 1-21. OT was administered intranasally (2 µg/µl, 7 days) to control and MS groups from PND 22-34. Plasma corticosterone (CORT) levels, anxiety-like behavior, sociability, learning and memory were measured in adolescent rats. In addition, extracellular evoked field excitatory postsynaptic potentials (fEPSP) were also recorded from hippocampal slices. MS induced higher plasma CORT levels and impaired social interaction, learning and memory. Moreover, MS reduced locomotor activity and increased anxiety-like behavior. Intranasal OT could overcome MS-induced deficits and promoted sociability, learning and memory of MS rats. OT also enhanced locomotor activity in the open field and decreased anxiety-like behavior. Obtained results showed that long term potentiation (LTP) was not induced in MS animals. However, OT injection overcame the MS-induced impairment in LTP generation in CA1 area of the hippocampus.

Effect of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide on cognitive deficits and hippocampal plasticity during nicotine withdrawal in rats.

Withdrawal from chronic nicotine has damaging effects on a variety of learning and memory tasks. Various Sulfonamides that act as carbonic anhydrase inhibitors have documented role in modulation of various cognitive, learning, and memory processing. We investigated the effects of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS) on nicotine withdrawal impairments in rats using Morris water maze (MWM), Novel object recognition, Passive avoidance, and open field tasks. Also, Brain-derived neurotrophic factor (BDNF) profiling and in vivo field potential recording were assessed. Rats were exposed to saline or chronic nicotine 3.8 mg/kg subcutaneously for 14 days in four divided doses, spontaneous nicotine withdrawal was induced by quitting nicotine for 72 h (hrs). Animals received 4-FBS at 20, 40, and 60 mg/kg after 72 h of withdrawal in various behavioral and electrophysiological paradigms. Nicotine withdrawal causes a deficit in learning and long-term memory in the MWM task. No significant difference was found in novel object recognition tasks among all groups while in passive avoidance task nicotine withdrawal resulted in a deficit of hippocampus-dependent fear learning. Anxiety like behavior was observed during nicotine withdrawal. Plasma BDNF level was reduced during nicotine withdrawal as compared to the saline group reflecting mild cognitive impairment, stress, and depression. Withdrawal from chronic nicotine altered hippocampal plasticity, caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results showed that 4-FBS at 40 and 60 mg/kg significantly prevented nicotine withdrawal-induced cognitive deficits in behavioral as well as electrophysiological studies. 4-FBS at 60 mg/kg upsurge nicotine withdrawal-induced decrease in plasma BDNF. We conclude that 4-FBS at 40 and 60 mg /kg effectively prevented chronic nicotine withdrawal-induced impairment in long term potentiation and cognitive performance.

Intergenerational effects of maternal separation on cognitive abilities of adolescent rats.

Early life adversity (ELA) is a predisposing factor for the development of behavioral and emotional disorders later in life. In humans, primates and rodents, interruption in the mother-infant relationships, and disorganized maternal care negatively influence appropriate behavioral responses and may cause cognitive deficits. Epidemiological studies suggest that ELA-induced behavioral alterations can be transmitted across generations. In this study, we investigated the cognitive abilities of male and female rats in the second filial (F2 ) generations whose mother, father, or both of their parents were undergoing a 180 min/day maternal separation (MS) paradigm during infancy (postnatal day (PND) 1-21). Cognitive abilities (in the open field, Morris water maze, and social interaction task) of F2 pups were tested during adolescence. Our results showed that although the mother-MS group of both sexes showed normal cognitive behavior, father-MS female pups showed more anxiety in the open field, and social interaction and spatial memory impaired in this group. These impairments were not pronounced in every detail in father-MS male pups. Moreover, rat pups that both parents experienced MS during infancy, showed normal cognitive behavior. Our data support the idea that MS-induced cognitive impairments could be transmitted across generations. Considerably, the experiences of one's parents could be inherited in the following generation in a sex-dependent manner.

What are the consequences of Methylphenidate exposure for maternally separated rats?

Methylphenidate (MPH) abuse is prevalent among youth. Drug abuse results in pain perception. We sought to investigate whether Maternal separation (MS) prone to MPH addiction. The next question was whether MPH abusers with MS differ in pain perception. We investigated the impact of MS on addiction and drug reward as well as pain perception following 5 days of MPH injection in males and females rats. Initially, rats underwent MS protocol of 3 hr daily for 21 days. Conditioned place preference (CPP) test was an attempt to investigate whether MS rats experience more reward with MPH. The protocol consisted of 10 min habituation on Day 1, conditioning on Day 2-Day 6 (5 mg per kg MPH injection in drug compartment and saline in saline compartment with 4 hr gap between injections) and 10 min test on Day 7. Furthermore, using another group, differences in pain perception were investigated after 5 days of daily MPH injection with 5 mg per kg. Sensory pain sensitivity was tested on PND 39 using tail flick and hotplate in MS and control groups with and without MPH exposure. Results indicated that female rats are equally prone to addiction in CPP. On the other hand, MS males experience a higher reward in CPP. In tail flick test, female MS rats exposed to MPH show a lower sensory pain threshold with similar MPH exposure. Experiencing MPH similarly declined hotplate pain perception in MS and controls in the females. Males, on the other hand, did not show any difference in sensory pain tests. According to results one can argue MS is detrimental. MS males experience more reward with MPH, females are equally addiction prone and MS females experience more pain in tail flick. On the other hand pain threshold can decline in hotplate test for both control and MS females that received MPH.

Environmental enrichment and pain sensitivity; a study in maternally separated rats.

Rodents are highly dependent on maternal care after birth. Maternal separation (MS) is an animal model for studying neglect and abuse. Depriving the pup of such care renders the animal with Hypothalamic-Pituitary-adrenal (HPA) dysfunction and these animals are more susceptible to anxiety and stress as well as poor cognition. These effects are due to abnormal brain development in these animals. We have tried to investigate how maternal separation can affect pain sensation and whether a non-pharmacological intervention such as enriched environment (EE) can restore an abnormal pain sensation. Animals were put into four groups MS, control (CTRL) and MS + EE and CTRL + EE groups that underwent EE after weaning until adulthood. These groups were tested for pain sensitivity with hot plate and tail flick for sensory pain and formalin for affect pain. The results showed that MS rats are more sensitive to pain in the hot plate test and formalin test, however, no significant difference was seen between groups for tail flick test. When MS rats experience EE their pain sensitivity is restored at the behavioral level. Further research is required to see how EE restores pain sensation in MS rats.

Effect of eugenol on lithium-pilocarpine model of epilepsy: behavioral, histological, and molecular changes.

OBJECTIVES: Epilepsy establishment gives rise to biochemical and morphological changes in the hippocampus. Oxidative stress, morphological changes, and mossy fiber sprouting (MFS) in the hippocampus underpin the epilepsy establishment. Eugenol is the main component of the essential oil extracted from cloves with the potential to modulate neuronal excitability. Therefore, we investigated the effect of eugenol on convulsive behavior, oxidative stress, and histological changes of the hippocampus in lithium-pilocarpine model of epilepsy. MATERIALS AND METHODS: Male Wistar rats weighing 220-250 g were divided into 4 groups; Control, Pilocarpine, Eugenol-Pilocarpine, and Eugenol. Oxidative stress markers were assayed by a biochemical method. Nissl and Timm staining were used to show neuronal survival and MFS, respectively. Behavioral convulsions were evaluated using the modified Racine scale. RESULTS: Eugenol decreased seizure stage and duration as well as mortality. Neuronal numbers were preserved by eugenol treatment in epileptic animals, while eugenol alone reduced the number by itself in all hippocampal sub-regions including DG, CA3, and CA1. Furthermore, eugenol alone increased MDA, GPx and SOD markers, while it increased MDA not only in combined treatment with pilocarpine but also in pilocarpine-treated animals. In contrast to MFS enhancement in naïve animals, eugenol partially reversed the MFS enhancement induced by pilocarpine. CONCLUSION: Eugenol could prevent behavioral convulsions and show neuroprotective effects through increasing neuronal survival probably by decreasing MFS and increasing the GPx antioxidant marker.