Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice.

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG activation and excitation of orexin neurons by systemic IGF-I are abrogated in old mice. Moreover, orthodromical responses of LH neurons are facilitated by either systemic or local IGF-I in young mice, but not in old ones. As orexin neurons of old mice show dysregulated IGF-I receptor (IGF-IR) expression, suggesting disturbed IGF-I sensitivity, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology.

Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. Results: We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. Conclusions: These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent.

Astrocytic IGF-IRs Induce Adenosine-Mediated Inhibitory Downregulation and Improve Sensory Discrimination.

Insulin-like growth factor-I (IGF-I) signaling plays a key role in learning and memory processes. While the effects of IGF-I on neurons have been studied extensively, the involvement of astrocytes in IGF-I signaling and the consequences on synaptic plasticity and animal behavior remain unknown. We have found that IGF-I induces long-term potentiation (LTPIGFI) of the postsynaptic potentials that is caused by a long-term depression of inhibitory synaptic transmission in mice. We have demonstrated that this long-lasting decrease in the inhibitory synaptic transmission is evoked by astrocytic activation through its IGF-I receptors (IGF-IRs). We show that LTPIGFI not only increases the output of pyramidal neurons, but also favors the NMDAR-dependent LTP, resulting in the crucial information processing at the barrel cortex since specific deletion of IGF-IR in cortical astrocytes impairs the whisker discrimination task. Our work reveals a novel mechanism and functional consequences of IGF-I signaling on cortical inhibitory synaptic plasticity and animal behavior, revealing that astrocytes are key elements in these processes.SIGNIFICANCE STATEMENT Insulin-like growth factor-I (IGF-I) signaling plays key regulatory roles in multiple processes of brain physiology, such as learning and memory. Yet, the underlying mechanisms remain largely undefined. Here we demonstrate that astrocytes respond to IGF-I signaling, elevating their intracellular Ca2+ and stimulating the release of ATP/adenosine, which triggers the LTD of cortical inhibitory synapses, thus regulating the behavioral task performance related to cortical sensory information processing. Therefore, the present work represents a major conceptual advance in our knowledge of the cellular basis of IGF-I signaling in brain function, by including for the first time astrocytes as key mediators of IGF-I actions on synaptic plasticity, cortical sensory information discrimination and animal behavior.

Cortical and hippocampal expression of inflammatory and intracellular signaling proteins in aged rats submitted to aerobic and resistance physical training.

Aging is often accompanied by an increase in pro-inflammatory markers. This inflammatory process is directly related to cellular dysfunctions that induce events such as the exacerbated activation of cell death signaling pathways. In the aged brain, dysregulation of the normal activities of neuronal cells compromises brain functions, thereby favoring the onset of neurodegenerative diseases and cognitive deficits. Interactions between various stimuli, such as stress, are responsible for the modulation of cellular processes and activities. Physical exercise is a controllable model of stress, largely used as a strategy for studying the physiological mechanisms of inflammatory responses and their consequences. However, different types of physical exercise promote different responses in the organism. The present study was designed to investigate the expression of inflammatory cytokines and chemokines, and expression and activation of intracellular signaling proteins (CREB, ERK, Akt, p70S6k, STAT5, JNK, NFkB e p38) in the cerebral cortex and hippocampal formation of aged rats submitted to aerobic and resistance exercise. Inflammatory analysis showed that aged rats that underwent resistance training had decreased cortical levels of RANTES and a reduction in the hippocampal levels of MIP-2 when compared with control animals (sedentary). No significant difference was detected in the cortical and hippocampal inflammatory response between aerobic and sedentary groups. However, when comparing the two training models (aerobic vs resistance), it was observed that aerobic training increased the cortical levels of IL-13, IL-6, IL-17α compared with resistance training. Regarding the signaling proteins, a significant increase in cortical expression of the proteins JNK, ERK and p70S6k was found in the aerobic group in relation to the sedentary group. No significant change in the cortical and hippocampal expression of signaling proteins was detected between resistance training and sedentary groups. Nevertheless, when training models were compared, it was observed that aerobic training increased cortical expression of the total proteins p38, ERK, Akt and p70S6k in relation to resistance training. Taken together, these results show that changes in the brain expression of inflammatory and cell survival proteins in aged rats depend on the type of physical training.

Hippocampal microRNA-mRNA regulatory network is affected by physical exercise.

BACKGROUND: It is widely known that physical activity positively affects the overall health and brain function. Recently, microRNAs (miRNAs) have emerged as potential regulators of numerous biological processes within the brain. These molecules modulate gene expression post-transcriptionally by inducing mRNA degradation and inhibiting the translation of target mRNAs. METHODS: To verify whether the procognitive effects of physical exercise are accompanied by changes in the activity of miRNA-mRNA network in the brain, differential expression analysis was performed in the hippocampus of control (CTL) and exercised (Ex) rats subjected to 4 weeks of treadmill exercise. Cognition was evaluated by a multiple trial inhibitory avoidance (MTIA) task and Illumina next-generation sequencing (NGS) was used for miRNA and mRNA profiling. RESULTS: Exercise improved memory retention but not acquisition in the MTIA task. It was observed that 4 miRNAs and 54 mRNAs were significantly altered in the hippocampus of Ex2 (euthanized 2 h after the last exercise bout) group when compared to CTL group. Bioinformatic analysis showed an inverse correlation between 3 miRNAs and 6 target mRNAs. The miRNAs miR-129-1-3p and miR-144-5p were inversely correlated to the Igfbp5 and Itm2a, respectively, and the miR-708-5p presented an inverse correlation with Cdkn1a, Per2, Rt1-a2. CONCLUSION: The exercise-induced memory improvements are accompanied by changes in hippocampal miRNA-mRNA regulatory network. GENERAL SIGNIFICANCE: Physical exercise can affect brain function through modulation of epigenetics mechanisms involving miRNA regulation.

Physical exercise alters the activation of downstream proteins related to BDNF-TrkB signaling in male Wistar rats with epilepsy.

There are a considerable number of studies concerning the behavioral effects of physical exercise on the epileptic brain; however, the intracellular signaling mechanisms involved remain unclear. We investigated the effects of aerobic exercise on hippocampal levels of brain-derived neurotrophic factor (BDNF), expression of its receptor tropomyosin receptor kinase B (TrkB), and activation of intracellular proteins related to BDNF-TrkB signaling in male Wistar rats with pilocarpine-induced epilepsy. Thirty days after the first spontaneous seizure, rats from the exercise group undertook a 30-day physical exercise program on the treadmill. Thereafter, BDNF levels, expression of TrkB, and activation of intracellular proteins were quantified by enzyme-linked immunosorbent assay, Western blotting, and multiplex assay, respectively. Statistical analyses were conducted using nonparametric tests. Rats with epilepsy presented decreased BDNF levels compared with control rats. BDNF levels increased significantly in the exercise group compared with the epileptic and control groups. Expression of full-length and truncated TrkB was increased in rats with epilepsy, and physical exercise restored its expression to control levels. RAC-alpha serine/threonine-protein kinase, mammalian target of rapamycin, and extracellular signal-regulated kinase activation were reduced in rats with epilepsy, and exercise increased activation compared with control and epilepsy groups. Increased cAMP response element binding protein activation was observed in the exercise group compared with the epilepsy group. Our findings indicate that the beneficial effects of exercise in the epileptic brain can be in part related to alterations in the activation of proteins related to the BDNF-TrkB signaling pathway.

Physical exercise as an epigenetic modulator of brain plasticity and cognition.

A large amount of evidence has demonstrated the power of exercise to support cognitive function, the effects of which can last for considerable time. An emerging line of scientific evidence indicates that the effects of exercise are longer lasting than previously thought up to the point to affect future generations. The action of exercise on epigenetic regulation of gene expression seem central to building an "epigenetic memory" to influence long-term brain function and behavior. In this review article, we discuss new developments in the epigenetic field connecting exercise with changes in cognitive function, including DNA methylation, histone modifications and microRNAs (miRNAs). The understanding of how exercise promotes long-term cognitive effects is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.

Aerobic exercise reduces hippocampal ERK and p38 activation and improves memory of middle-aged rats.

Aging is often accompanied by cognitive decline, memory impairment, and an increased susceptibility to neurodegenerative disorders. Although the physiological processes of aging are not fully understood, these age-related changes have been interpreted by means of various cellular and molecular theories. Among these theories, alterations in the intracellular signaling pathways associated with cell growth, proliferation, and survival have been highlighted. Based on these observations and on recent evidence showing the beneficial effects of exercise on cognitive function in the elderly, we investigated the cell signaling pathways in the hippocampal formation of middle-aged rats (18 months old) submitted to treadmill exercise over 10 days. To do this, we evaluated the hippocampal activation of intracellular signaling proteins linked to cell growth, proliferation, and survival, such as Akt, mTOR, p70S6K, ERK, CREB, and p38. We also explored the cognitive performance (inhibitory avoidance) of middle-aged rats. It was found that physical exercise reduces ERK and p38 activation in the hippocampal formation of aged rats, when compared to the control group. The hippocampal activation and expression of Akt, mTOR, p70S6K, and CREB were not statistically different between the groups. It was also observed that aged rats from the exercise group exhibited better cognitive performance in the inhibitory avoidance task (aversive memory) than aged rats from the control group. Our results indicate that physical exercise reduces intracellular signaling pathways linked to inflammation and cell death (i.e., ERK and p38) and improves memory in middle-aged rats.

Resistance Exercise Reduces Seizure Occurrence, Attenuates Memory Deficits and Restores BDNF Signaling in Rats with Chronic Epilepsy.

Epilepsy is a disease characterized by recurrent, unprovoked seizures. Cognitive impairment is an important comorbidity of chronic epilepsy. Human and animal model studies of epilepsy have shown that aerobic exercise induces beneficial structural and functional changes and reduces the number of seizures. However, little is yet understood about the effects of resistance exercise on epilepsy. We evaluated the effects of a resistance exercise program on the number of seizures, long-term memory and expression/activation of signaling proteins in rats with epilepsy. The number of seizures was quantified by video-monitoring and long-term memory was assessed by an inhibitory avoidance test. Using western blotting, multiplex and enzyme-linked immunosorbent assays, we determined the effects of a 4-week resistance exercise program on IGF-1 and BDNF levels and ERK, CREB, mTOR activation in the hippocampus of rats with epilepsy. Rats with epilepsy submitted to resistance exercise showed a decrease in the number of seizures compared to non-exercised epileptic rats. Memory deficits were attenuated by resistance exercise. Rats with epilepsy showed an increase in IGF-1 levels which were restored to control levels by resistance exercise. BDNF levels and ERK and mTOR activation were decreased in rats with epilepsy and resistance exercise restored these to control levels. In conclusion, resistance exercise reduced seizure occurrence and mitigated memory deficits in rats with epilepsy. These resistance exercise-induced beneficial effects can be related to changes in IGF-1 and BDNF levels and its signaling protein activation. Our findings indicate that the resistance exercise might be included as complementary therapeutic strategy for epilepsy treatment.

A single bout of resistance exercise improves memory consolidation and increases the expression of synaptic proteins in the hippocampus.

Over the past decade, several studies have indicated that chronic resistance exercise (i.e., strength training, weight lifting, etc.) is beneficial for brain health and cognitive function. However, little is known about the effects of a single bout of resistance exercise on brain function, particularly on memory consolidation. Therefore, the purpose of the present study is to examine the effects of a single bout of resistance exercise applied immediately after the training of fear conditioning on memory consolidation and on the expression of IGF-1 and synaptic proteins in the hippocampus. Male Wistar rats were familiarized with climbing a ladder without a load for 3 days and randomly assigned into control (CTL) and resistance exercise (RES) groups. The RES group was subjected to a single bout of resistance exercise applied immediately after fear conditioning training. Subsequently, the animals were tested for contextual (24 h) and tone (48 h) fear memory. Another group of animals were subjected to a single bout of resistance exercise and euthanized 24 h later for hippocampal analysis of IGF-1 and synaptic proteins (synapsin I, synaptophysin, and PSD-95). The exercised rats improved contextual but not tone fear memory. Hippocampal IGF-1 was not altered by resistance exercise. However, the levels of synapsin I, synaptophysin, and PSD-95 increased significantly in the RES group. The results suggested that a single bout of resistance exercise applied immediately after fear conditioning could improve contextual memory, probably through the activation of pre- and postsynaptic machinery required for memory consolidation. © 2016 Wiley Periodicals, Inc.

Maternal Exercise during Pregnancy Increases BDNF Levels and Cell Numbers in the Hippocampal Formation but Not in the Cerebral Cortex of Adult Rat Offspring.

Clinical evidence has shown that physical exercise during pregnancy may alter brain development and improve cognitive function of offspring. However, the mechanisms through which maternal exercise might promote such effects are not well understood. The present study examined levels of brain-derived neurotrophic factor (BDNF) and absolute cell numbers in the hippocampal formation and cerebral cortex of rat pups born from mothers exercised during pregnancy. Additionally, we evaluated the cognitive abilities of adult offspring in different behavioral paradigms (exploratory activity and habituation in open field tests, spatial memory in a water maze test, and aversive memory in a step-down inhibitory avoidance task). Results showed that maternal exercise during pregnancy increased BDNF levels and absolute numbers of neuronal and non-neuronal cells in the hippocampal formation of offspring. No differences in BDNF levels or cell numbers were detected in the cerebral cortex. It was also observed that offspring from exercised mothers exhibited better cognitive performance in nonassociative (habituation) and associative (spatial learning) mnemonic tasks than did offspring from sedentary mothers. Our findings indicate that maternal exercise during pregnancy enhances offspring cognitive function (habituation behavior and spatial learning) and increases BDNF levels and cell numbers in the hippocampal formation of offspring.

The beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling is impaired by anabolic androgenic steroids.

Previous studies have shown that strength exercise improves memory and increases expression of a myriad of proteins involved on neuronal survival and synaptic plasticity in the hippocampus. Conversely, chronic exposure to supraphysiological levels of anabolic androgenic steroids (AAS) can induce psychiatric abnormalities, cognitive deficits, impair neurotransmission, alter the levels of neurotrophic factors, decrease cell proliferation and neurogenesis, and enhance neuronal cell death. In the present study, we investigated the effects of the AAS nandrolone decanoate (ND) administration during a strength exercise program on cell proliferation, apoptotic status and brain-derived neurotrophic factor (BDNF) expression in the rat hippocampus. Adult male Wistar rats were subjected to 4 weeks of progressive strength exercise in a vertical ladder apparatus with or without daily doses (5.0 mg/kg, SC) of ND. Immunohistochemistry analysis revealed that strength exercise increased significantly the number of Ki-67-positive cells (a cell proliferation marker) in dentate gyrus (DG) of hippocampus. However, this effect was abrogated when strength exercise was combined with ND. Although western blot analysis of whole hippocampus showed no significant differences in Bax and Bcl-2 protein expression among groups, the immunoreactivity of the pro-apoptotic protein Bax was significantly increased in DG, CA1 and CA3 hippocampal subfields of sedentary rats treated with ND. Moreover, the increase in the immunoreactivity of anti-apoptotic protein Bcl-2 (DG and CA3) induced by strength exercise was diminished by ND. There were no significant differences in BDNF expression among experimental groups. Therefore, the present findings suggest that the beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling are impaired by ND.

Differential effects of exercise intensities in hippocampal BDNF, inflammatory cytokines and cell proliferation in rats during the postnatal brain development.

It has been established that low intensities of exercise produce beneficial effects for the brain, while high intensities can cause some neuronal damage (e.g. exacerbated inflammatory response and cell death). Although these effects are documented in the mature brain, the influence of exercise intensities in the developing brain has been poorly explored. To investigate the impact of exercise intensity in developing rats, we evaluated the hippocampal level of brain derived neurotrophic factor (BDNF), inflammatory cytokines (TNFα, IL6 and IL10) and the occurrence of hippocampal cell degeneration and proliferation at different stages of postnatal brain development of rats submitted to two physical exercise intensities. To this point, male rats were divided into different age groups: P21, P31, P41 and P51. Each age group was submitted to two exercise intensities (low and high) on a treadmill over 10 consecutive days, except the control rats. We verified that the density of proliferating cells was significantly higher in the dentate gyrus of rats submitted to low-intensity exercise from P21 to P30 compared with high-intensity exercise and control rats. A significant increase of proliferative cell density was found in rats submitted to high-intensity exercise from P31 to P40 when compared to low-intensity exercise and control rats. Elevated hippocampal levels of IL6 were detected in rats submitted to high-intensity exercise from P21 to P30 compared to control rats. From P41 to P50 period, higher levels of BDNF, TNFα and IL10 were found in the hippocampal formation of rats submitted to high-intensity exercise in relation to their control rats. Our data show that exercise-induced neuroplastic effects on BDNF levels and cellular proliferation in the hippocampal region are dependent on exercise intensity and developmental period. Thus, exercise intensity is an inflammation-inducing factor and exercise-induced inflammatory response during the postnatal brain development is also related to developmental stage. Our findings indicate that neuroplastic changes induced by exercise in developing rats depend on both age and training intensity.

Aerobic exercise attenuates inhibitory avoidance memory deficit induced by paradoxical sleep deprivation in rats.

The deleterious effects of paradoxical sleep deprivation (SD) on memory processes are well documented. Physical exercise improves many aspects of brain functions and induces neuroprotection. In the present study, we investigated the influence of 4 weeks of treadmill aerobic exercise on both long-term memory and the expression of synaptic proteins (GAP-43, synapsin I, synaptophysin, and PSD-95) in normal and sleep-deprived rats. Adult Wistar rats were subjected to 4 weeks of treadmill exercise training for 35 min, five times per week. Twenty-four hours after the last exercise session, the rats were sleep-deprived for 96 h using the modified multiple platform method. To assess memory after SD, all animals underwent training for the inhibitory avoidance task and were tested 24h later. The aerobic exercise attenuated the long-term memory deficit induced by 96 h of paradoxical SD. Western blot analysis of the hippocampus revealed increased levels of GAP-43 in exercised rats. However, the expression of synapsin I, synaptophysin, and PSD-95 was not modified by either exercise or SD. Our results suggest that an aerobic exercise program can attenuate the deleterious effects of SD on long-term memory and that this effect is not directly related to changes in the expression of the pre- and post-synaptic proteins analyzed in the study.

Animal model for progressive resistance exercise: a detailed description of model and its implications for basic research in exercise / Modelo animal de exercício resistido progressivo: descrição detalhada do modelo e a sua implicação à pesquisa básica com exercício

The Several animal models have been proposed for resistance training. In addition, the results of these studies have been highly variable. Some of the studies have used negative reinforcement, electric shock or food deprivation to motivate the learning of the task. Features such as conditioning through electric shock may undermine the significance of the results or even prevent the model from being successfully executed. Due to these reasons, in this study we propose to use an adaptation of the vertical ladder climbing model for progressive resistance training in rats, albeit with a unique feature to ensure the homogeneity of the study groups: a period of adaptation to the apparatus without any negative reinforcement followed by a subsequent pairing of animals based on their ability to learn. The animals were distributed in the experimental group who were subjected to 8 weeks of a progressive resistance exercise protocol and the control group. After 8wks, the gastrocnemius, soleus, flexor digitorum longus (FDL), and plantaris muscles were removed and the cross-sectional area morphometry was obtened. The animals from experimental group showed hypertrophy [F(4, 15)=17,404, P < 0.001] for gastrocnemius [60% of hipertrophy; Control (2628,64 ± 348,50) versus Experimental (4207,77 ± 1256,52); ES=1.96; Power=0,86]; FDL [35% of hipertrophy; Control (2753,80 ± 359,54) versus Experimental (3711,84 ± 279,45); ES=2.99; Power=0.99] and plantaris [38% of hipertrophy; Control (2730,44 ± 320,56) versus Experimental (3767,30 ± 625,80); ES=2.19; Power=0.92], without modifications for soleus. All animals successfully completed the 8-week progressive resistance training program without any injuries, abandonment or death. Negative reinforcements such as electric shock were not required at any time in the experiment. In conclusion, we showed an adaptation of the previus model for progressive resistance training in rats. A period of adaptation to the apparatus without any negative ...

Alguns modelos animais de treinamento resistido vem sendo proprostos ao longo do tempo, com resultados variáveis e por vezes conflitantes. Contudo, todos eles utilizam reforço negativo ao ensinar os animais o aprendizado da tarefa, por exemplo, choque elétrico ou privação alimentar e tais condicionamentos podem interferir de algma forma na variável estudada. Por estas razões, este estudo propões uma adaptação de um modelo de treinamento resistido de subida em escada vertical já existente, mas com um período de familiarização ao equipamento, sem choque elétrico, seguido pela distribuição de acordo com o desempenho do aprendizado de subida em escada. Os animais foram distribuídos em: grupo experimental (submetido a oito semanas de treinamento resistido) e grupo controle. Após a intervenção, os músculos gastrocnemius, soleus, flexor digitorum longus (FDL), and plantaris foram removidos e a moformetria das fibras muculares foi realizada. Os animais do grupo experimental mostraram hipertrofia [F(4, 15)=17,404, P < 0.001] nos músculos: gastrocnemius [60% de hipertrofia; Control (2628,64 ± 348,50) versus Experimental (4207,77 ± 1256,52); ES=1.96; Power=0,86]; FDL [35% de hipertrofia; Control (2753,80 ± 359,54) versus Experimental (3711,84 ± 279,45); ES=2.99; Power=0.99] e plantaris [38% de hipertrofia; Control (2730,44 ± 320,56) versus Experimental (3767,30 ± 625,80); ES=2.19; Power=0.92], sem alterações no soleus. Ainda, todos os animais completaram o protocolo sem qualquer lesão, abandono ou morte. Reforço negativo como choque elétrico ou de outra natureza não foi realizado por todo o experimento. Concluindo, foi mostrado uma adaptação de modelo de treinamento resistido progressivo em ratos. Um período de adaptação ao aparato sem qualquer reforço negativo somado a um período de adaptação baseado na distribuição de acordo com o desempenho do aprendizado de subida em escada, pode ser uma estratégia ao protocolo original. Foi mostrado também hipetrofia ...

A strength exercise program in rats with epilepsy is protective against seizures.

The beneficial effects of physical exercise on epilepsy, such as a decreased seizure frequency, have been observed following aerobic exercise programs in both clinical and experimental studies. However, it is not well clarified whether other types of exercise, including strength exercise, can provide similar benefits for epilepsy. Forty four animals with epilepsy were continuously monitored 24 h a day for 60 days and divided into two periods of 30 days. The first period was used to determine the number of seizures before beginning the physical exercise program, and the second period was utilized to determine the number of seizures during the strength training. The mean frequency of seizures in the control and SHAM groups increased significantly from period 1 to period 2. Although the frequency of seizures did not change significantly between the two periods of 30 days of observation in the strength exercise group, a significant reduction in the seizure frequency was observed compared with the control and SHAM groups in period 2. Our study demonstrated that a strength exercise program exerted a significant influence on the seizure frequency in animals with epilepsy and strengthens the observed beneficial effect of exercise on epilepsy that has been demonstrated in animal studies. The finding of this nonclinical study can open a new window to verify the beneficial contribution of strength exercise in epilepsy. Further experimental and clinical investigations are necessary to explore the extent to which strength exercise interferes with the epileptic condition.