Exposure to Sub-Lethal Doses of Permethrin Is Associated with Neurotoxicity: Changes in Bioenergetics, Redox Markers, Neuroinflammation and Morphology.

Permethrin (PERM) is a member of the class I family of synthetic pyrethroids. Human use has shown that it affects different systems, with wide health dysfunctions. Our aim was to determine bioenergetics, neuroinflammation and morphology changes, as redox markers after subacute exposure to PERM in rats. We used MDA determination, protein carbonyl assay, mitochondrial O2 consumption, expression of pro-inflammatory cytokines and a deep histopathological analysis of the hippocampus. PERM (150 mg/kg and 300 mg/kg body weight/day, o.v.) increased lipoperoxidation and carbonylated proteins in a dose-dependent manner in the brain regions. The activities of antioxidant enzymes glutathione peroxidase, reductase, S-transferase, catalase, and superoxide dismutase showed an increase in all the different brain areas, with dose-dependent effects in the cerebellum. Cytokine profiles (IL-1ß, IL-6 and TNF-α) increased in a dose-dependent manner in different brain tissues. Exposure to 150 mg/kg of permethrin induced degenerated and/or dead neurons in the rat hippocampus and induced mitochondrial uncoupling and reduction of oxidative phosphorylation and significantly decreased the respiratory parameters state 3-associated respiration in complex I and II. PERM exposure at low doses induces reactive oxygen species production and imbalance in the enzymatic antioxidant system, increases gene expression of pro-inflammatory interleukins, and could lead to cell damage mediated by mitochondrial functional impairment.

Effects of time-of-day on the concentration of defined excitatory and inhibitory amino acids in the cerebrospinal fluid of rats: a microdialysis study.

Amino acid neurotransmitters are responsible for many physiological and pathological processes, and their cerebral concentrations respond to external influences such as the light-dark cycle and to the synthesis, release, and recapture rhythms and form part of the biochemical relationships derived from excitatory-inhibitory (E/I), glutamine-glutamate sum (GLX), glutamatergic processing (glutamine-glutamate ratio) and excitotoxic indexes. The changes in these variables during a 24-h period (1 day) are important because they allow organisms to adapt to external stimuli and form part of physiological processes. Under pathological conditions, the damage produced by acute events may depend on diurnal variations. Therefore, it is important to analyze the extracellular levels of amino acids as well as the above-mentioned indexes over a 24-h period. We focused on determining the cerebrospinal fluid levels of different amino acid neurotransmitters, and the E/I, GLX, glutamatergic processing and excitotoxic indexes, determined by microdialysis over a 24-h cycle. Our results showed significant changes during the 24-h light/dark cycle. Specifically, we found increments in the levels of glutamate (325%), GABA (550%), glutamine (300%), glycine (194%), alanine (304%) and the GLX index (263%) throughout the day, and the maximum levels of glutamate, glutamine, glycine, and alanine were obtained during the last period of the light period. In conclusion, the concentration of some amino acid neurotransmitters and the GLX index show variations depending on the light-dark cycle.

Diurnal Variation Induces Neurobehavioral and Neuropathological Differences in a Rat Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) induces two types of brain damage: primary and secondary. Damage initiates a series of pathophysiological processes, such as metabolic crisis, excitotoxicity with oxidative stress-induced damage, and neuroinflammation. The long-term perpetuation of these processes has deleterious consequences for neuronal function. However, it remains to be elucidated further whether physiological variation in the brain microenvironment, depending on diurnal variations, influences the damage, and consequently, exerts a neuroprotective effect. Here, we established an experimental rat model of TBI and evaluated the effects of TBI induced at two different time points of the light-dark cycle. Behavioral responses were assessed using a 21-point neurobehavioral scale and the cylinder test. Morphological damage was assessed in different regions of the central nervous system. We found that rats that experienced a TBI during the dark hours had better behavioral performance than those injured during the light hours. Differences in behavioral performance correlated with less morphological damage in the perilesional zone. Moreover, certain brain areas (CA1 and dentate gyrus subregions of the hippocampus) were less prone to damage in rats that experienced a TBI during the dark hours. Our results suggest that diurnal variation is a crucial determinant of TBI outcome, and the hour of the day at which an injury occurs should be considered for future research.

Neuroinflamación: el ying-yang de la neuroinmunología / Neuroinflammation: the ying-yang of neuroimmunology

Resumen El área de la neuroinmunología es un campo que se encuentra en gran desarrollo y que tiene como objetivo el entender las interacciones fisiológicas entre el sistema nervioso central (SNC) y el sistema inmune periférico, llegándose a encontrar que estas relaciones son más importantes de lo que se creía y que por lo tanto son 2 sistemas íntimamente conectados y con una gran dinámica. Por otro lado, la neuroinflamación es activada después de cualquier reto inmunológico, tanto dentro como fuera del SNC, y que puede llevar a generar tanto respuestas enfocadas a la limitación del daño y la restauración del tejido, como a ser un riesgo para el desarrollo de enfermedades neurodegenerativas en el caso de que este estímulo permanezca de manera crónica.

Abstract The field of neuroimmunology has recently had a development, and its primary goal is to understand the physiological interactions between the central nervous system (CNS) and the peripheral immune system. Various data has found that these relations are more important than what was previously thought. Also, that both systems are highly dynamic and are intimately connected. On the other hand, neuroinflammation is activated after any immune challenge, both inside and outside the CNS, leading to responses focused on limiting tissue damage and restoration; as well as being a risk for developing neurodegenerative diseases when this stimulus remains chronic.

Diurnal variation of NMDA receptor expression in the rat cerebral cortex is associated with traumatic brain injury damage.

OBJECTIVE: Data from our laboratory suggest that recovery from a traumatic brain injury depends on the time of day at which it occurred. In this study, we examined whether traumatic brain injury -induced damage is related to circadian variation in N-methyl-D-aspartate receptor expression in rat cortex. RESULTS: We confirmed that traumatic brain injury recovery depended on the time of day at which the damage occurred. We also found that motor cortex N-methyl-D-aspartate receptor subunit NR1 expression exhibited diurnal variation in both control and traumatic brain injury-subjected rats. However, this rhythm is more pronounced in traumatic brain injury-subjected rats, with minimum expression in those injured during nighttime hours. These findings suggest that traumatic brain injury occurrence times should be considered in future clinical studies and when designing neuroprotective strategies for patients.

Models used in the study of traumatic brain injury.

Traumatic brain injury (TBI) is a contemporary health problem and a leading cause of mortality and morbidity worldwide. Survivors of TBI frequently experience disabling long-term changes in cognition, sensorimotor function, and personality. A crucial step in understanding TBI and providing better treatment has been the use of models to mimic the event under controlled conditions. Here, we describe the known head injury models, which can be classified as whole animal (in vivo), in vitro, and mathematical models. We will also review the ways in which these models have advanced the knowledge of TBI.

Effect of Intermediate-Frequency Repetitive Transcranial Magnetic Stimulation on Recovery following Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) represents a significant public health concern and has been associated with high rates of morbidity and mortality. Although several research groups have proposed the use of repetitive transcranial magnetic stimulation (rTMS) to enhance neuroprotection and recovery in patients with TBI, few studies have obtained sufficient evidence regarding its effects in this population. Therefore, we aimed to analyze the effect of intermediate-frequency rTMS (2 Hz) on behavioral and histological recovery following TBI in rats. Male Wistar rats were divided into six groups: three groups without TBI (no manipulation, movement restriction plus sham rTMS, and movement restriction plus rTMS) and three groups subjected to TBI (TBI only, TBI plus movement restriction and sham rTMS, and TBI plus movement restriction and rTMS). The movement restriction groups were included so that rTMS could be applied without anesthesia. Our results indicate that the restriction of movement and sham rTMS per se promotes recovery, as measured using a neurobehavioral scale, although rTMS was associated with faster and superior recovery. We also observed that TBI caused alterations in the CA1 and CA3 subregions of the hippocampus, which are partly restored by movement restriction and rTMS. Our findings indicated that movement restriction prevents damage caused by TBI and that intermediate-frequency rTMS promotes behavioral and histologic recovery after TBI.

Cystatin C has a dual role in post-traumatic brain injury recovery.

Cathepsin B is one of the major lysosomal cysteine proteases involved in neuronal protein catabolism. This cathepsin is released after traumatic injury and increases neuronal death; however, release of cystatin C, a cathepsin inhibitor, appears to be a self-protective brain response. Here we describe the effect of cystatin C intracerebroventricular administration in rats prior to inducing a traumatic brain injury. We observed that cystatin C injection caused a dual response in post-traumatic brain injury recovery: higher doses (350 fmoles) increased bleeding and mortality, whereas lower doses (3.5 to 35 fmoles) decreased bleeding, neuronal damage and mortality. We also analyzed the expression of cathepsin B and cystatin C in the brains of control rats and of rats after a traumatic brain injury. Cathepsin B was detected in the brain stem, cerebellum, hippocampus and cerebral cortex of control rats. Cystatin C was localized to the choroid plexus, brain stem and cerebellum of control rats. Twenty-four hours after traumatic brain injury, we observed changes in both the expression and localization of both proteins in the cerebral cortex, hippocampus and brain stem. An early increase and intralysosomal expression of cystatin C after brain injury was associated with reduced neuronal damage.

Does the neuroprotective role of anandamide display diurnal variations?

The endocannabinoid system is a component of the neuroprotective mechanisms that an organism displays after traumatic brain injury (TBI). A diurnal variation in several components of this system has been reported. This variation may influence the recovery and survival rate after TBI. We have previously reported that the recovery and survival rate of rats is higher if TBI occurs at 1:00 than at 13:00. This could be explained by a diurnal variation of the endocannabinoid system. Here, we describe the effects of anandamide administration in rats prior to the induction of TBI at two different times of the day: 1:00 and 13:00. We found that anandamide reduced the neurological damage at both times. Nevertheless, its effects on bleeding, survival, food intake, and body weight were dependent on the time of TBI. In addition, we analyzed the diurnal variation of the expression of the cannabinoid receptors CB1R and CB2R in the cerebral cortex of both control rats and rats subjected to TBI. We found that CB1R protein was expressed more during the day, whereas its mRNA level was higher during the night. We did not find a diurnal variation for the CB2R. In addition, we also found that TBI increased CB1R and CB2R in the contralateral hemisphere and disrupted the CB1R diurnal cycle.

Sleep deprivation has a neuroprotective role in a traumatic brain injury of the rat.

During the process of a brain injury, responses to produce damage and cell death are activated, but self-protective responses that attempt to maintain the integrity and functionality of the brain are also activated. We have previously reported that the recovery from a traumatic brain injury (TBI) is better in rats if it occurs during the dark phase of the diurnal cycle when rats are in the waking period. This suggests that wakefulness causes a neuroprotective role in this type of injury. Here we report that 24h of total sleep deprivation after a TBI reduces the morphological damage and enhances the recovery of the rats, as seen on a neurobiological scale.

Neuroprotección y traumatismo craneoencefálico / Neuroprotection and traumatic brain injury

Durante un proceso de lesión cerebral, por ejemplo en un traumatismo craneoencefálico, se activan respuestas que inducen daño cerebral o muerte celular; sin embargo, también se inducen respuestas de protección que intentan mantener la integridad y funcionalidad del cerebro; esto se conoce como neuroprotección. Efectivamente, posterior a un TCE, se desencadenan mecanismos que traen como consecuencia liberación de neurotransmisores excitadores tales como el glutamato, lo que provoca una entrada masiva de Ca²+ en las neuronas, activación de proteasas, lipasas, sintasa de óxido nítrico, endonucleasas, producción de radicales libres y potencialmente necrosis o apoptosis. Aunque hay reportes de sustancias neuro o cerebroprotectoras desde hace más de 50 años, es al final de la década de los ochenta del siglo pasado cuando comienza a aparecer un gran número de publicaciones tratando de entender los mecanismos neuroprotectores desencadenados por un insulto al cerebro. En este trabajo revisamos brevemente el concepto, la epidemiologia y los diversos agentes que se han utilizado para disminuir el daño causado por un traumatismo craneoencefálico.

During a process of brain injury, e.g. head injury, responses to induce brain damage and / or cell death are activated, but also protective responses that attempt to maintain the integrity and functionality of the brain are induced. This is known as neuroprotection. Indeed a head injury triggers mechanisms that result in release of excitatory neurotransmitters such as glutamate, which causes an influx of Ca²+ into neurons, activation of proteases, lipases, nitric oxide synthase, endonucleases, free radicals production and potentially necrosis and / or apoptosis. Although the brain or neuroprotective substances research has more than 50 years, is at the end of the decade of 80's of last century when it began to appear a large number of publications trying to understand the neuroprotective mechanisms triggered by an insult to the brain. In this paper we briefly review the concept, epidemiology and strategies that have been used to minimize the damage caused by brain injury.