Traumatic brain injury (TBI) is a leading cause of long-term neurological disability worldwide. Among its complications, post-traumatic seizures (PTS) can exacerbate injury outcomes and increase the risk of developing post-traumatic epilepsy (PTE), particularly in severe cases. This study investigated the role of thrombin/PAR1 signaling in early post-traumatic hyperexcitability and evaluated whether prior physical exercise could mitigate excitability-related mechanisms, such as blood–brain barrier (BBB) disruption and ionic imbalance following TBI. The investigation comprised two separate experiments using the lateral fluid-percussion injury (LFPI) model. In the first, male rats underwent LFPI and were assessed via electroencephalographic (EEG) recordings, followed by biochemical analysis of the ipsilateral hippocampus six hours post-injury. In the second, animals were randomly assigned to sedentary or exercise groups. After four weeks of aerobic training, animals received a PAR1 antagonist for one week and then underwent the same injury and evaluation protocols. Our results show that prior physical exercise and PAR1 antagonism significantly reduced LFPI-induced epileptiform activity, as evidenced by lower EEG total power, amplitude, and interictal spike frequency. These interventions also preserved BBB integrity, reduced thrombin extravasation, modulated PAR1 and downstream PKC/P70S6K signaling, and mitigated astrocytic reactivity and Na⁺/K⁺-ATPase dysfunction. Furthermore, both treatments inhibited GABAergic dysregulation and decreased pro-inflammatory cytokine levels, thereby attenuating the neurotoxic post-injury environment. These findings highlight the critical role of thrombin/PAR1 signaling in PTS and support the neuroprotective potential of physical exercise in modulating post-traumatic excitability, offering a promising therapeutic strategy for preventing PTE.

The Na+,K + -ATPase (NKA) enzyme is crucial for maintaining neuronal excitability, yet its response to acute physical exertion in the central nervous system remains largely unexplored. Here, we report a volume-dependent modulation of NKA activity in the cerebral cortex of rats subjected to a strenuous swimming protocol. A single bout of exhaustive exercise (1 set) significantly decreased total NKA activity and increased blood-brain barrier (BBB) permeability (albumin extravasation) without altering lipid peroxidation. Conversely, repeated exposure (3 sets, 72-h intervals) triggered an acute compensatory response: it prevented BBB disruption and significantly upregulated total NKA, α1, and α2/3 isoform activities. This functional upregulation occurred independently of total NKA protein expression but was accompanied by increased p-PKC/PKC and p-CaMKII/CaMKII phosphorylation ratios. These findings indicate that while an initial bout of exhaustive exercise compromises cortical NKA activity and neurovascular integrity, recurrent acute exertion induces rapid neuroprotective and enzymatic adaptations driven by post-translational kinase signaling.

Traumatic brain injury (TBI) affects millions globally and increasingly associates with cardiovascular disease risk through mechanisms involving autonomic nervous system dysfunction, neuroinflammation, oxidative stress, and hypothalamic-pituitary axis disruption. However, the precise molecular pathways remain incompletely understood. This review synthesizes current evidence on TBI-induced cardiovascular dysfunction and explores physical exercise as a therapeutic intervention. We conducted a comprehensive literature narrative review of experimental and clinical studies investigating cardiovascular complications following TBI and exercise-based interventions. TBI triggers a cascade of molecular events leading to autonomic imbalance, chronic inflammation, and oxidative damage that collectively increase cardiovascular risk. Physical exercise emerges as a promising intervention through its capacity to modulate inflammatory processes, restore autonomic balance, and enhance synaptic plasticity. However, optimal timing, intensity, and duration of exercise protocols remain undefined. Understanding heart-brain communication pathways post-TBI is crucial for developing targeted interventions. Physical exercise shows therapeutic potential, but standardized protocols are needed to optimize cardiovascular outcomes in TBI patients.

In this study, we demonstrate for the first time that post-injury creatine supplementation (300 mg/kg, p.o.) administered for two weeks attenuates blood-brain barrier disruption, cortical lesion volume (by ∼60%), spatial memory deficits (reducing escape latency by ∼50% in the Barnes maze), hippocampal theta/delta rhythm alterations, and epileptiform activity in 35-day-old male rats subjected to severe fluid percussion injury (FPI). In the hippocampus, the FPI protocol did not cause overt neuronal loss-particularly of parvalbumin-positive neurons in the CA1 and CA2 regions-but it significantly reduced creatine levels and induced marked mitochondrial dysfunction. These alterations were evidenced by impaired MTT reduction, disrupted mitochondrial membrane potential (Δψ), decreased SDH activity, inhibition of respiratory chain complexes I-III, COX, citrate synthase (CS), and CKm activity, together with increased mitochondrial oxidative stress (enhanced DCFH-DA oxidation, elevated 4-hydroxynonenal levels, depletion of free -SH groups, and reduced GSH levels). We propose a mechanistic cascade wherein mitochondrial dysfunction and elevated oxidative stress drive the inhibition of Na⁺,K⁺-ATPase, which in turn contributes to neuronal hyperexcitability and cognitive deficits. Creatine's ability to maintain mitochondrial integrity directly interrupts this cascade, protecting against dysfunctions in these essential ion-gradient systems. In conclusion, post-injury creatine supplementation preserves mitochondrial function, maintains Na⁺,K⁺-ATPase activity, and prevents epileptiform activity and cognitive deficits, highlighting creatine as a promising strategy to mitigate secondary injury. However, these findings must be interpreted in light of certain limitations, including the use of a male-only cohort, a single time-point assessment, and the correlational nature of the proposed mechanistic pathways, warranting further investigation.

Objective: Adolescence is a critical developmental window during which physical activity can exert long-lasting effects on brain function and health. However, the molecular impact of structured exercise during this period remains poorly understood. This study investigated whether a five-week progressive swimming protocol during adolescence induces behavioral and molecular adaptations in the rat cerebral cortex Materials and Methods: Twelve male Wistar rats were divided into Sedentary and Exercise groups. The Exercise group underwent a swimming protocol from postnatal day 41 (P41) to P73. From P76 to P79, animals underwent behavioral tests. On P80, they were euthanized for blood and cerebral cortex collection. Plasma irisin levels were measured by ELISA, and cortical proteins were analyzed by Western blotting. Results: Sedentary rats showed higher body weight than exercised rats. While exercise increased locomotor and exploratory tendencies, it did not affect memory. Exercised animals had elevated cortical BDNF and NRF2, with no change in irisin levels Conclusion: Structured swimming exercise during adolescence induces cortical molecular adaptations related to neuroplasticity and redox regulation, even in the absence of overt behavioral changes, supporting the hypothesis that early-life physical activity enhances latent brain resilience mechanisms that may be critical under future physiological or pathological challenges.

Traumatic brain injury (TBI) is a burdensome condition frequently associated with an increased risk of psychiatric disorders. Although the exact molecular signaling pathways have not yet been fully defined, the compromised integrity of functional brain networks in regions such as the prefrontal cortex and anterior cingulate cortex has been linked to persistent symptoms, including depression, fatigue, and sleep disorders. Understanding how TBI affects neural physiology enables the development of effective interventions. One such strategy may be physical exercise, which promotes neural repair and behavioral rehabilitation after TBI. However, there are caveats to consider when interpreting the effects of physical exercise on TBI-induced mental health issues. This review will highlight the main findings from the literature investigating how different physical exercise protocols affect the progression of TBI-induced depression, fatigue, and sleep disturbances. Furthermore, we aim to explore potential neurobiological pathways that explain how physical exercise influences depression, fatigue, and sleep following TBI.

Repeated concussions during critical stages of brain development can lead to lasting neural and behavioral changes. This study characterized the consequences of recurrent, spaced concussions using a clinically relevant adolescent Wistar rat model. Male rats were subjected to ten spaced concussions via a weight-drop model during adolescence (P42-P73) and subsequently underwent neurobehavioral, neurochemical, and histological analysis. Behaviorally, the concussion protocol induced hyperactivity in the open-field test and produced specific deficits in the Novel Object Location task; in contrast, performance was unimpaired in the Novel Object Recognition and Barnes Maze tests. These behavioral outcomes were accompanied by disruptions to cortical dopaminergic and GABAergic systems, including reduced dopamine D2 receptor levels, lower monoamine oxidase-A activity, and decreased brain-derived neurotrophic factor (BDNF) and increased gamma-aminobutyric acid decarboxylase 67 (GAD67) expression. Concurrently, glial fibrillary acidic protein (GFAP) expressions were elevated in specific corticolimbic regions. Importantly, these alterations occurred without severe injury markers, such as loss of consciousness or albumin extravasation. Our findings demonstrate that spaced concussive events during adolescence are sufficient to produce distinct behavioral and neurochemical deficits. This work highlights dopaminergic dysfunction as a key etiological factor and potential therapeutic target for impairments following repeated concussions in the developing brain.

Pelizaeus-Merzbacher-like disease (PMLD, OMIM #608804) is an autosomal recessive hypomyelinating leukodystrophy caused by homozygous variants in the GJC2 gene. It usually presents in the first months of life with nystagmus, developmental delay, and diffuse hypomyelination on brain magnetic resonance imaging (MRI). We report a case of a 3-year-old boy that presented with nystagmus and global developmental delay. MRI showed diffuse hypomyelination, including the cerebellum. Pelizaeus-Merzbacher disease (PMD) was suspected; however, no pathological variants of the PLP1 gene were found. Exome sequencing found variants in the GJC2 gene, leading to a diagnosis of PMLD. The combination of global developmental delay, hypomyelination, and nystagmus in a child should raise suspicion of PMD and PMLD. Unlike PMD, however, hypomyelination of the brainstem and cerebellum are frequently seen and brainstem auditory evoked potentials are usually normal in PMLD. The latter has an overall better prognosis than the former as well. Epidemiological studies on leukodystrophies have found conflicting results on which disease is more common. However, PMLD is a rare leukodystrophy and both PMLD and PMD should be considered in any child with developmental delay, hypomyelination, and nystagmus.

Over the past few decades, research involving brain-gut crosstalk has rapidly evolved to become an important topic in preclinical and clinical research. In the health and sports environment, a paradigm shift in the bidirectional interactions between the gut–brain is essential for exercise-induced rehabilitation strategies and preventive interventions. However, there are caveats to consider when interpreting the mechanism by which physical exercise can exert its effects on the brain–gut axis, given that different exercise protocols (e.g., duration and intensity) have variable effects on this crosstalk. Therefore, an integrative perspective of the exercise-induced gut–brain communication pathway will be discussed in this chapter.

Status epilepticus (SE) is a medical emergency associated with high mortality and morbidity. Na+, K+-ATPase, is a promising therapeutic target for SE, given its critical role in regulation of neuron excitability and cellular homeostasis. We investigated the effects of a Na+, K+-ATPase-activating antibody (DRRSAb) on short-term electrophysiological and behavioral consequences of pilocarpine-induced SE. Rats were submitted to pilocarpine-induced SE, followed by intranasal administration (2 μg/nostril). The antibody increased EEG activity following SE, namely, EEG power in theta, beta, and gamma frequency bands, assessed by quantitative analysis of EEG power spectra. One week later, DRRSAb-treated animals displayed less behavioral hyperreactivity in pick-up tests and better performance in novel object recognition tests, indicating that the intranasal administration of this Na+, K+-ATPase activator immediately after SE improves behavioral outcomes at a later time point. These results suggest that Na+, K+-ATPase activation warrants further investigation as an adjunctive therapeutic strategy for SE.

A paradigm shift in the understanding of bidirectional interactions between peripheral and central nervous systems is essential for development of rehabilitation and preventive interventions based on physical exercise. Although a causal relationship has not been completely established, modulation of voltage-dependent ion channels (Ca2+, Cl−, K+, Na+, lactate-, H+) in skeletal and neuronal cells provides opportunities to maintain force production during exercise and reduce the risk of disease. However, there are caveats to consider when interpreting the effects of physical exercise on this bidirectional axis, since exercise protocol details (e.g., duration and intensity) have variable effects on this crosstalk. Therefore, an integrative perspective of the skeletal muscle and brain’s communication pathway is discussed, and the role of physical exercise on such communication highway is explained in this review.

Aflatoxin B1 (AFB1) is the most common toxic mycotoxin that contaminates food. The treatment of its intoxication and the management of contaminations are a constant subject of health agendas worldwide. However, such efforts are not always enough to avoid population intoxication. Our objective was to investigate whether intermittent exposure to AFB1 would cause any impairment in biochemical and behavioral parameters, intending to simulate an irregular consumption. Male Wistar rats received four AFB1 administrations (250 μg/kg) by intragastric route separated by a 96-h interval. Toxicity was evaluated using behavioral tests (open field, object recognition, nest construction, marble burying, and splash test), biochemical markers of oxidative stress (cerebral cortex, hippocampus, liver, and kidneys), and plasma parameters of hepatic and renal functions. The intermittent exposure caused no modification in body weight gain as well as in organ weight. Both control and AFB1 groups presented similar profiles of behavior to all tests performed. Furthermore, AFB1 administrations alter neither antioxidant defenses nor markers of oxidation in all assayed tissues and in the plasma markers of hepatic and renal functions. Therefore, AFB1 intermittent administration did not cause its common damage from exposure to this toxicant, which must be avoided, and additional studies are required.

Epilepsy is characterized by a predisposition to generate recurrent and spontaneous seizures; it affects millions of people worldwide. Status epilepticus (SE) is a severe type of seizure. In this context, screening potential treatments is very important. In the present study, we evaluated the beneficial effects of rosmarinic acid (RA) in pilocarpine-induced in vitro and in vivo models of epileptiform activity. Using an in vitro model in combined entorhinal cortex–hippocampal from Wistar rats we evaluated the effects of RA (10 µg/mL) on the lactate release and a glucose fluorescent analogue, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NDBG), after incubation in high potassium aCSF supplemented or not with pilocarpine. In the in vivo model, SE was induced in male C57BL/6 mice by pilocarpine. At 1, 24, and 48 h after the end of SE mice were treated with RA (30 mg/kg/v.o.). We evaluated the neuromotor impairment by neuroscore tests and protein carbonyl levels in the cerebral cortex. In both in vitro models, RA was able to decrease the stimulated lactate release, while no effect on 2-NBDG uptake was found. RA has beneficial effects in models of epileptiform activity in vivo and in vitro. We found that RA treatment attenuated SE-induced neuromotor impairment at the 48 h timepoint. Moreover, post-SE treatment with RA decreased levels of protein carbonyls in the cerebral cortex of mice when compared to their vehicle-treated counterparts. Importantly, RA was effective in a model of SE which is relevant for the human condition. The present data add to the literature on the biological effects of RA, which could be a good candidate for add-on therapy in epilepsy.

Aspartame (ASP) is a common sweetener, but studies show it can harm the nervous system, causing learning and memory deficits. β-caryophyllene (BCP), a natural compound found in foods, including bread, coffee, alcoholic beverages, and spices, has already described as a neuroprotector agent. Remarkably, ASP and BCP are commonly consumed, including in the same meal. Therefore, considering that (a) the BCP displays plenty of beneficial effects; (b) the ASP toxicity; and (c) that they can be consumed in the same meal, this study sought to investigate if the BCP would mitigate the memory impairment induced by ASP in rats and investigate the involvement of the brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrKB) signaling pathway and acetylcholinesterase (AChE) activity. Young male Wistar rats received ASP (75 mg/kg; i.g.) and/or BCP (100 mg/kg; i.p.) once daily, for 14 days. At the end of the treatment, the animals were evaluated in the open field and object recognition tests. The cerebral cortex and hippocampus samples were collected for biochemical and molecular analyses. Results showed that the BCP effectively protected against the cognitive damage caused by ASP in short and long-term memories. In addition, BCP mitigated the increase in AChE activity caused by ASP. Molecular insights revealed augmented BDNF and TrKB levels in the hippocampus of rats treated with BCP, indicating greater activation of this pathway. In conclusion, BCP protected against ASP-induced memory impairment. AChE activity and the BDNF/TrkB signaling pathway seem to be potential targets of BCP modulatory role in this study.

Abstract Despite the number of studies supporting the neuroprotective role of creatine in pathophysiology caused by traumatic brain injuries, there is insufficient knowledge of how this ergogenic compound may potentially affect brain-injury complications in adolescence. Thus, we hypothesized that creatine supplementation after a TBI could prevent from deleterious neurological effects such as memory deficits, mitochondrial disfunction and epileptiform activity. Our experimental data revealed, for the first time, that creatine supplementation (300 mg/kg, po) for two weeks after neuronal injury protected against spatial memory dysfunction (Barnes maze test), disruption of hippocampal theta/delta activity, and spontaneous epileptiform activity in 35-day-old rats submitted to severe fluid percussion injury (FPI). Interestingly, the FPI protocol did not cause cell loss (especially parvalbumin-positive neurons) in the CA1 and CA2/CA3 areas but induced mitochondria dysfunction (MTT, Δψ, SDH, complex II, COX, CS, CKm activity inhibition, and CKm immunoreactivity decrease), and mitochondrial oxidative stress (DCFH-DA oxidation, increased 4-hydroxynonenal levels, free -SH groups, and lower GSH levels). Creatine’s ability to maintain mitochondrial integrity protected against dysfunctions in molecular systems involved in cellular energy homeostasis (decreased PGC1 and TFAM immunoreactivity), Na+,K+-ATPase activity inhibition, and proteins related to brain plasticity (decreased BDNF, TrkB, and pCREB/CREB immunoreactivity) after FPI. These data suggest that epileptiform activity and cognitive dysfunction in young rats may, at least partly, result from alterations in surviving neurons interfering with creatine-induced secondary injury, which may be an excellent therapeutic strategy against toxicity induced by traumatic brain injury.

We report a 24-year-old male with blepharophimosis, psychomotor retardation, brachycephaly, microstomia, immobile face, high arched palate, single palmar crease, kyphoscoliosis, talipes equinovarus, inguinal hernia, pyloric stenosis, recurrent infections, bilateral camptodactyly, wide-set eyes, decreased muscle mass, hypotonia, exotropia, and ptosis in the left eye, growth retardation, multiple congenital contractures, and hyporreflexia. Contractures improved with aging, but intellectual disability and blepharophimosis remained. He also presented epilepsy, outbursts of laughter, and predisposition to drug adverse effects (skin lesions with carbamazepine and secondary parkinsonism).

Several studies demonstrated the toxicity of aspartame (ASP) and aflatoxin B1 (AFB1 ) in preclinical models. Although the majority of these reports assessed the toxic effects of each substance separately, their concomitant exposure and hazardous consequences are scarce. Importantly, the deleterious effects at the central nervous system caused by ASP and AFB1 co-exposure are rarely addressed. We evaluated if concomitant exposure to AFB1 and ASP would cause behavioral impairment and alteration in oxidative status of the brain in male rats. Animals received once a day for 14 days AFB1 (250 µg/kg, intragastric gavage [i.g.]), ASP (75 mg/kg, i.g.), or both substances (association). On day 14, they were subjected to behavioral evaluation, and biochemical and molecular parameters of oxidative status were measured in the cerebral cortex and hippocampus. In the open field test, AFB1 and combination treatments modified the motor, exploratory, and grooming behavior. In the splash test, all treatments caused a reduction in grooming time compared to the control group. An increase in thiobarbituric acid-reactive substances content induced by AFB1 and combination treatments was observed. The antioxidant defenses (vitamin C, nonprotein sulfhydryl, and ferric reducing antioxidant power) were impaired in all groups compared to control. Regarding molecular evaluation, mitochondrial superoxide dismutase-2 immunoreactivity decreased after AFB1 or ASP exposition in the hippocampus. Thus, co-exposure to ASP and AFB1 was potentially more toxic because it aggravated behavioral impairments and oxidative status disbalance in comparison to the groups that received only ASP or AFB1 . Therefore, our data suggest that those substances caused a disruption in brain homeostasis.

Treatment-resistant depression is a common psychiatric disorder that can lead to significant disability and decreased quality of life for patients.In recent years, there has been growing interest in the combination of intravenous ketamine and electroconvulsive therapy (ECT) for the treatment of treatmentresistant depression.Ketamine is an anesthetic that is an N-methyl-D-aspartate (NMDA) receptor antagonist that also has antidepressant properties and has been used to treat treatment-resistant depression.ECT is a treatment for depression that involves applying electric current to the brain to induce therapeutic seizures.Recent studies have shown that the combination of intravenous ketamine and ECT can be an effective treatment for treatment-resistant depression.Although more research is still needed to fully understand the efficacy and safety of the combination of intravenous ketamine and ECT for the treatment of treatment-resistant depression, combination therapy may be a promising option for patients who do not respond to other treatments.

Sports-related concussions are particularly common during adolescence, and there is insufficient knowledge about how recurrent concussions in this phase of life alter the metabolism of essential structures for memory in adulthood. In this sense, our experimental data revealed that seven recurrent concussions (RC) in 35-day-old rats decreased short-term and long-term memory in the object recognition test (ORT) 30 days after injury. The RC protocol did not alter motor and anxious behavior and the immunoreactivity of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Recurrent concussions induced the inflammatory/oxidative stress characterized here by increased glial fibrillary acidic protein (GFAP), interleukin 1β (IL 1β), 4-hydroxynonenal (4 HNE), protein carbonyl immunoreactivity, and 2',7'-dichlorofluorescein diacetate oxidation (DCFH) levels and lower total antioxidant capacity (TAC). Inhibited Na+,K+-ATPase activity (specifically isoform α2/3) followed by Km (Michaelis-Menten constant) for increased ATP levels and decreased immunodetection of alpha subunit of this enzyme, suggesting that cognitive impairment after RC is caused by the inability of surviving neurons to maintain ionic gradients in selected targets to inflammatory/oxidative damage, such as Na,K-ATPase activity.