Epilepsy is a common neurological condition characterized by recurrent convulsive episodes and abnormal neuronal hyperexcitability, affecting approximately 65 million individuals worldwide, with a disproportionately higher prevalence in developing nations [1]. Beyond its immediate neurological manifestations, epilepsy presents multifaceted challenges encompassing health, social, psychological, and economic burdens, particularly among women of reproductive age who constitute nearly 40% of the epileptic population globally (Kassahun Bekele et al., 2024).

Maternal epilepsy represents a critical clinical concern due to its profound implications for both maternal health and fetal neurodevelopment. Mounting evidence demonstrates that offspring born to mothers with epilepsy exhibit significantly increased risks of adverse neurodevelopmental outcomes, including cognitive impairments, developmental delays, and structural brain abnormalities [2, 3]. Of particular concern are the documented cerebellar structural alterations in these children, which directly compromise motor coordination (MC)—a fundamental neuromotor competency essential for optimal physical and cognitive development [4, 5]. MC encompasses the synchronized integration of multiple motor units and neural pathways to execute complex, coordinated movements efficiently. This multifaceted motor skill serves as a cornerstone for childhood development, underpinning not only basic locomotor activities but also higher-order cognitive-motor integration processes crucial for academic performance and social competence [6, 7]. The disruption of MC development in offspring of epileptic mothers thus represents a significant public health concern with long-lasting implications for quality of life and functional independence.

Current therapeutic approaches predominantly rely on antiepileptic drugs (AEDs), which, despite their efficacy in seizure control, pose substantial teratogenic risks during pregnancy. Epidemiological studies consistently report 2–3 fold increased rates of major congenital malformations among AED-exposed pregnancies, including cardiac defects, orofacial clefts, neural tube defects, and skeletal abnormalities [8–10]. These findings underscore the urgent need for safe, effective non-pharmacological interventions that can mitigate seizure severity while minimizing developmental risks to the developing fetus.

Emerging evidence suggests that structured physical exercise represents a promising complementary therapeutic modality for epilepsy management. Clinical investigations demonstrate that regular aerobic exercise significantly reduces seizure frequency, enhances neuroplasticity, and improves overall quality of life in epileptic patients [11, 12]. Mechanistic studies in animal models reveal that exercise-induced neuroprotection involves multiple pathways, including enhanced hippocampal neurogenesis, reduced amygdalar hyperexcitability, and optimization of synaptic plasticity [13, 14]. Importantly, recent investigations suggest that maternal exercise during pregnancy exerts beneficial effects on offspring neurodevelopment through multiple mechanisms, including enhanced placental function, improved fetal oxygenation, and upregulation of neurotrophic factors [15, 16]. Furthermore, maternal physical activity appears to promote favorable epigenetic modifications that may protect against neurodevelopmental disorders [17, 18].

However, the specific intersection between maternal exercise, epilepsy management, and offspring motor coordination outcomes remains inadequately explored, representing a critical knowledge gap in maternal-fetal medicine. Given the well-documented benefits of exercise on seizure control and the emerging evidence for maternal exercise-induced neuroprotection in offspring, we hypothesized that structured aerobic exercise during pregnancy in epileptic mothers could provide dual benefits: (1) reducing maternal seizure severity and duration, and (2) preventing or ameliorating motor coordination deficits in offspring. This investigation addresses a crucial research gap by examining whether maternal exercise intervention during pregnancy can serve as an effective, safe strategy to mitigate the adverse neurodevelopmental consequences of maternal epilepsy on offspring motor coordination, potentially offering a novel therapeutic approach for improving long-term outcomes in this vulnerable population.

The chronic kindling model of epilepsy was induced in all 60 female mice. Each mouse received a daily intraperitoneal injection of 35 mg/kg pentylenetetrazole (PTZ) for 30 consecutive days. During this period, the mortality rate was 28.33%. All 43 surviving mice were successfully kindled, as confirmed by their seizure scores on the modified Racine scale during the final three injections. Only mice exhibiting seizure scores of 4 (clonic-tonic seizures with turning over) or 5 (generalized clonic-tonic seizures with turning onto their back) were deemed successfully kindled and proceeded to the next phase [5].

Following the kindling process, the 43 epileptic female mice were paired with healthy male mice for mating. Successful copulation was confirmed by the presence of a vaginal plug, which marked Gestational Day 0 (GD 0). A total of 26 mice became pregnant, resulting in an infertility rate of approximately 39.53%. These 26 pregnant mice were then randomly divided into four experimental groups.

The 26 pregnant mice were randomly assigned to one of four groups:

For non-exercising groups (SAL and PTZ), mice were placed in their home cages for the duration of the exercise protocol to minimize the potential stress of handling and a novel environment.

The two exercise groups (SAL + Exe and PTZ + Exe) underwent a treadmill running protocol from Gestational Day 1 (GD 1) to GD 20. The protocol started with a 3-minute warm-up at 8 m/min. The main session began at a speed of 10 m/min for 10 minutes and gradually increased to 12 m/min for 30 minutes by the final sessions. This regimen is considered a moderate-intensity exercise protocol for mice, and electric shock stimulation was used sparingly to encourage running [19–21].

The duration of PTZ-induced seizures was measured in the pregnant mice of the PTZ and PTZ + Exe groups on Gestational Days 6, 12, and 18. Seizure duration was defined as the total time spent in convulsive activity within a 15-minute observation period following the PTZ injection [22].

The current study investigated the protective effects of maternal aerobic exercise during pregnancy on maternal convulsive activity and subsequent motor coordination (MC) deficits in preadolescent male offspring following prenatal seizure exposure. Our findings reveal several key points: (1) maternal seizures induced by pentylenetetrazole (PTZ) significantly increased the stillbirth rate and impaired MC in the offspring; (2) maternal aerobic exercise significantly reduced the duration of convulsive activity on gestational days 12 and 18; and (3) this exercise intervention effectively mitigated the MC deficits in offspring, restoring their performance to levels comparable to the control group. These results collectively highlight the therapeutic potential of maternal exercise as a complementary strategy to improve both maternal and offspring outcomes in the context of epilepsy.

Our observation that maternal PTZ-induced seizures lead to an increased stillbirth rate is consistent with prior research linking maternal epilepsy and antiepileptic drug (AED) use to adverse pregnancy outcomes [24]. Previous studies have also reported higher perinatal mortality rates in offspring of epileptic mothers [25]. Although our exercise intervention did not significantly reduce the stillbirth rate, the observed trend toward lower mortality in the exercise group suggests a potential protective effect that warrants further investigation with a larger sample size. This protective effect may be linked to the exercise-induced reduction in seizure duration, which could theoretically mitigate the frequency and severity of hypoxia and neuroinflammation associated with convulsive episodes.

A central finding of this study is that moderate-intensity aerobic exercise effectively reduced the duration of maternal seizures. This is in agreement with existing literature that demonstrates the anti-epileptic effects of physical activity [11, 12, 14]. Several potential neurobiological mechanisms may explain this effect. Exercise is known to modulate neuronal excitability by enhancing the activity of the inhibitory neurotransmitter GABA, particularly in the hippocampus [14]. Furthermore, physical activity elevates Brain-Derived Neurotrophic Factor (BDNF), which in turn increases the expression of parvalbumin (PV) in interneurons [14, 26]. PV-interneurons are crucial for regulating network excitability, and their dysfunction is implicated in epileptogenesis [27, 28]. Additionally, regular exercise has been shown to counteract the neuroinflammation often associated with epilepsy, possibly by inhibiting microglial activation and phagocytosis [29–31]. The reduction in seizure duration in our study could also be linked to a decrease in stress sensitivity, as exercise is known to buffer against stress and reduce circulating corticosterone levels, a hormone that can increase seizure susceptibility [12, 32].

The most compelling finding of our study is the protective effect of maternal exercise on offspring MC. We observed that prenatal seizure exposure significantly impaired MC in preadolescent male mice, confirming previous research in adult male offspring [4, 5]. This deficiency can be attributed to the well-documented consequences of prenatal hypoxia and inflammation resulting from maternal seizures, which negatively impact fetal brain development [4, 33, 34]. These insults can lead to decreased levels of key neurotrophic factors like BDNF, which is essential for the proper development and function of the cerebellum and the broader motor system [35–37].

Our results demonstrate that maternal aerobic exercise was able to fully counteract these MC deficits. This is likely mediated by the exercise-induced increase in neurotrophic factors, particularly BDNF. Exercise during pregnancy can elevate BDNF levels in the mother's bloodstream, and this neurotrophin is capable of crossing the placental barrier to influence fetal neurodevelopment [38, 39]. Increased fetal BDNF can promote cerebellar granule cell migration, enhance Purkinje cell responses, and optimize synaptic plasticity in motor circuits—all of which are critical for developing and refining motor skills [40–42]. Beyond BDNF, maternal exercise has been shown to reduce neuroinflammation and oxidative stress in offspring, which are two key mechanisms by which seizures cause neuronal damage and functional impairment [43–45]. This anti-inflammatory effect is possibly mediated by an increase in anti-inflammatory factors such as Peptide YY [45].

In conclusion, this study provides strong evidence that maternal aerobic exercise during pregnancy can serve as a dual-action therapeutic strategy. It not only reduces maternal seizure severity but also protects offspring from the neurodevelopmental consequences of prenatal seizure exposure, specifically impairments in motor coordination. Our findings underscore the importance of promoting physical activity in pregnant women with epilepsy as a safe, non-pharmacological approach to improve both maternal health and long-term offspring outcomes. Future research should focus on exploring the precise molecular pathways underlying these protective effects and investigating the long-term impacts of such interventions into adulthood.