Evaluating Sex Steroid Hormone Neuroprotection in Spinal Cord Injury in Animal Models: Is It Promising in the Clinic?

The primary mechanism of traumatic spinal cord injury (SCI) comprises the initial mechanical trauma due to the transmission of energy to the spinal cord, subsequent deformity, and persistent compression. The secondary mechanism of injury, which involves structures that remained undamaged after the initial trauma, triggers alterations in microvascular perfusion, the liberation of free radicals and neurotransmitters, lipid peroxidation, alteration in ionic concentrations, and the consequent cell death by necrosis and apoptosis. Research in the treatment of SCI has sought to develop early therapeutic interventions that mitigate the effects of these pathophysiological mechanisms. Clinical and experimental evidence has demonstrated the therapeutic benefits of sex-steroid hormone administration after traumatic brain injury and SCI. The administration of estradiol, progesterone, and testosterone has been associated with neuroprotective effects, better neurological recovery, and decreased mortality after SCI. This review evaluated evidence supporting hormone-related neuroprotection over SCI and the possible underlying mechanisms in animal models. As neuroprotection has been associated with signaling pathways, the effects of these hormones are observed on astrocytes and microglia, modulating the inflammatory response, cerebral blood flow, and metabolism, mediating glutamate excitotoxicity, and their antioxidant effects. Based on the current evidence, it is essential to analyze the benefit of sex steroid hormone therapy in the clinical management of patients with SCI.

Daytime-Restricted Feeding Ameliorates Oxidative Stress by Increasing NRF2 Transcriptional Factor in the Rat Hippocampus in the Pilocarpine-Induced Acute Seizure Model.

Seizure-mediated oxidative stress is a crucial mechanism in the pathophysiology of epilepsy. This study evaluated the antioxidant effects of daytime-restricted feeding (DRF) and the role of the Nrf2 signaling pathway in a lithium-pilocarpine model seizure model that induces status epilepticus (SE). We performed a lipoperoxidation assay and dihydroethidium fluorescence to measure oxidative stress markers in the hippocampus (malondialdehyde and reactive oxygen species). The protein content of Nrf2 and its downstream protein SOD2 was evaluated using Western blotting. The cellular distribution of the Nrf2 and SOD2 proteins in the pyramidal cell layer of both the CA1 and CA3 hippocampal subfields and astrocytes (GFAP marker) were quantified using immunofluorescence and immunohistochemistry, respectively. Our results indicate that DRF reduced the malondialdehyde levels and the production of reactive oxygen species. Furthermore, a significant increase in Nrf2 and SOD2 protein content was observed in animals subjected to restrictive diet. In addition, DRF increased the relative intensity of the Nrf2 fluorescence in the perinuclear and nuclear compartments of pyramidal neurons in the CA1 subfield. Nrf2 immunoreactivity and the astrocyte marker GFAP also increased their colocalization under DRF conditions. Additionally, SOD2 immunoreactivity was increased in CA1 pyramidal neurons but not in the CA3 region. Our findings suggest that DRF partially prevents oxidative stress by increasing the Nrf2 transcriptional factor and the SOD2 enzyme during the development of SE.

Study of genetic variants and their clinical significance in Mexican pediatric patients with epilepsy.

BACKGROUND: The use of novel and accurate techniques to identify genetic variants (with or without a record in the National Center for Biotechnology Information (NCBI) database) improves diagnosis, prognosis, and therapeutics for patients with epilepsy, especially in populations for whom such techniques exist. The aim of this study was to find a genetic profile in Mexican pediatric epilepsy patients by focusing on ten genes associated with drug-resistant epilepsy (DRE). METHODS: This was a prospective, analytical, cross-sectional study of pediatric patients with epilepsy. Informed consent was granted by the patients' guardians or parents. Genomic DNA from the patients was sequenced using next-generation sequencing (NGS). For statistical analysis, Fisher's exact, Chi-square or Mann-Whitney U, and OR (95% CI) tests were performed, with significance values of p < 0.05. RESULTS: Fifty-five patients met the inclusion criteria (female 58.2%, ages 1-16 years); 32 patients had controlled epilepsy (CTR), and 23 had DRE. Four hundred twenty-two genetic variants were identified (71.3% with a known SNP registered in the NCBI database). A dominant genetic profile consisting of four haplotypes of the SCN1A, CYP2C9, and CYP2C19 genes was identified in most of the patients studied. When comparing the results between patients with DRE and CTR, the prevalence of polymorphisms in the SCN1A (rs10497275, rs10198801, and rs67636132), CYP2D6 (rs1065852), and CYP3A4 (rs2242480) genes showed statistical significance (p = 0.021). Finally, the number of missense genetic variants in patients in the nonstructural subgroup was significantly higher in DRE than in CTR (1 [0-2] vs. 3 [2-4]; p = 0.014). CONCLUSIONS: The Mexican pediatric epilepsy patients included in this cohort presented a characteristic genetic profile infrequent in the Mexican population. SNP rs1065852 (CYP2D6*10) is associated with DRE, especially with nonstructural damage. The presence of three genetic alterations affecting the CYP2B6, CYP2C9, and CYP2D6 cytochrome genes is associated with nonstructural DRE.

Short-term administration of tibolone reduces inflammation and oxidative stress in the hippocampus of ovariectomized rats fed high-fat and high-fructose.

Inflammation and oxidative stress are critical events involved in neurodegeneration. In animal models, it has been shown that chronic consumption of a hypercaloric diet, which leads to inflammatory processes, affects the hippocampus, a brain region fundamental for learning and memory processes. In addition, advanced age and menopause are risk factors for neurodegeneration. Hormone replacement therapy (HRT) ameliorates menopause symptoms. Tibolone (TB), a synthetic hormone, exerts estrogenic, progestogenic and androgenic effects on different tissues. We aimed to determine the effect of short-term TB administration on oxidative stress and inflammation markers in the hippocampus of ovariectomized rats fed a high-fat-and-fructose diet (HFFD). Adult female rats were ovariectomized (OVX) and fed standard diet or HFFD-consisting of 10% lard supplemented chow and 20% high-fructose syrup in the drinking water-and administered vehicle or TB (1 mg/kg for seven days). Finally, we administered hormone receptor antagonists (MPP, RU486 or FLU) to each of the OVX + HFFD + TB groups. Bodyweight, triglycerides and cholesterol, oxidative stress and inflammation markers, and the activity and expression of antioxidant enzymes were quantified in the hippocampus of each experimental group. We observed that short-term TB administration significantly reduced body weight, AGEs, MDA levels, increased SOD and GPx activity, improved GSH/GSSG ratio, and reduced IL-6 and TNF-α. Our findings suggest that short-term administration of TB decreases oxidative stress and reduces inflammation caused by HFFD and early estrogenic decline. These effects occurred via estrogen receptor alpha.

Tibolone Improves Memory and Decreases the Content of Amyloid-ß Peptides and Tau Protein in the Hippocampus of a Murine Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) affects women more than men and consequently has been associated with menopause. Tibolone (TIB) has been used as a hormone replacement therapy to alleviate climacteric symptoms. Neuroprotective effects of TIB have also been reported in some animal models. OBJECTIVE: This study aimed to assess the effect of TIB on memory and Aß peptides and tau protein content in the hippocampus and cerebellum of transgenic 3xTgAD ovariectomized mice. METHODS: Three-month-old female mice were ovariectomized. Ten days after surgery, animals were divided into four groups: wild-type (WT)+vehicle; WT+TIB (1 mg/kg); 3xTgAD+vehicle; and 3xTgAD+TIB (1 mg/kg). TIB was administered for three months, and memory was evaluated using the object-in-context recognition task. Subsequently, animals were decapitated, and the hippocampus and cerebellum were dissected. Using commercial ELISA kits, these brain structures were homogenized in a PBS buffer for quantifying Aß40 and Aß42 and phosphorylated and total tau.ResultsA long-term memory deficit was observed in the 3xTgAD+vehicle group. In contrast, TIB treatment improved long-term memory in the 3xTgAD+TIB group than those treated with vehicle (p < 0.05). Furthermore, TIB treatment decreased Aß and tau content in the hippocampus of 3xTgAD mice compared to vehicle-treated groups (p < 0.05). No significant changes were observed in the cerebellum. CONCLUSION: Chronic treatment with TIB showed neuroprotective effects and delayed AD neuropathology in the 3xTgAD mice. Our results support hormone replacement therapy with TIB in menopausal women for neuroprotection.

Cannabidiol Reduces Short- and Long-Term High Glutamate Release after Severe Traumatic Brain Injury and Improves Functional Recovery.

This study aimed to determine if orally administered cannabidiol (CBD) lessens the cortical over-release of glutamate induced by a severe traumatic brain injury (TBI) and facilitates functional recovery. The short-term experiment focused on identifying the optimal oral pretreatment of CBD. Male Wistar rats were pretreated with oral administration of CBD (50, 100, or 200 mg/kg) daily for 7 days. Then, extracellular glutamate concentration was estimated by cortical microdialysis before and immediately after a severe TBI. The long-term experiment focused on evaluating the effect of the optimal treatment of CBD (pre- vs. pre- and post-TBI) 30 days after trauma. Sensorimotor function, body weight, and mortality rate were evaluated. In the short term, TBI induced a high release of glutamate (738% ± 173%; p < 0.001 vs. basal). Oral pretreatment with CBD at all doses tested reduced glutamate concentration but with higher potency at when animals received 100 mg/kg (222 ± 33%, p < 0.01 vs. TBI), an effect associated with a lower mortality rate (22%, p < 0.001 vs. TBI). In the long-term experiment, the TBI group showed a high glutamate concentration (149% p < 0.01 vs. SHAM). In contrast, animals receiving the optimal treatment of CBD (pre- and pre/post-TBI) showed glutamate concentrations like the SHAM group (p > 0.05). This effect was associated with high sensorimotor function improvement. CBD pretreatment, but not pre-/post-treatment, induced a higher body weight gain (39% ± 2.7%, p < 0.01 vs. TBI) and lower mortality rate (22%, p < 0.01 vs. TBI). These results support that orally administered CBD reduces short- and long-term TBI-induced excitotoxicity and facilitated functional recovery. Indeed, pretreatment with CBD was sufficient to lessen the adverse sequelae of TBI.

Down Regulation of Catsper1 Expression by Calmodulin Inhibitor (Calmidazolium): Possible Implications for Fertility.

The CatSper channel localizes exclusively in the flagella of sperm cells. The Catsper1 protein, together with three pore units, is essential for the CatSper Channel formation, which produces flagellum hyperactivation and confers sperm fertility. Catsper1 expression is dependent on Sox transcription factors, which can recognize in vitro at least three Sox binding sites on the promoter. Sox transcription factors have calmodulin-binding domains for nuclear importation. Calmodulin (CaM) is affected by the specific inhibitor calmidazolium (CMZ), which prevents the nuclear transport of Sox factors. In this work, we assess the regulation of the Catsper1 promoter in vivo by Sox factors in the murine testis and evaluate the effects of the inhibitor calmidazolium on the expression of the Casper genes, and the motility and fertility of the sperm. Catsper1 promoter has significant transcriptional activity in vivo; on the contrary, three Sox site mutants in the Catsper1 promoter reduced transcriptional activity in the testis. CaM inhibition affects Sox factor nuclear transport and has notable implications in the expression and production of Catsper1, as well as in the motility and fertility capability of sperm. The molecular mechanism described here might conform to the basis of a male contraceptive strategy acting at the transcriptional level by affecting the production of the CatSper channel, a fundamental piece of male fertility.

Aberrant Connection Formation and Glia Involvement in the Progression of Pharmacoresistant Mesial Temporal Lobe Epilepsy.

Epilepsy is the most common chronic neurological disease, affecting approximately 65 million people worldwide, with mesial temporal lobe epilepsy (mTLE) being the most common type, characterized by the presence of focal seizures that begin in the hippocampus, and subsequently generalize to structures such as the cerebral cortex. It is estimated that approximately 40% of patients with mTLE develop drug resistance (DR), whose pathophysiological mechanisms remain unclear. The neuronal network hypothesis is one attempt to understand the mechanisms underlying resistance to antiepileptic drugs (AEDs), since recurrent seizure activity generates excitotoxic damage and activation of neuronal death and survival pathways that, in turn, promote the formation of aberrant neuronal networks. This review addresses the mechanisms that are activated, perhaps as compensatory mechanisms in response to the neurological damage caused by epileptic seizures, but that affect the formation of aberrant connections that allow the establishment of inappropriate circuits. On the other hand, glia seems to have a relevant role in post-seizure plasticity, thus supporting the hypothesis of the neuronal network in drug-resistant epilepsy, which has been proposed for ELT.

Plasma Levels of Amyloid-ß Peptides and Tau Protein in Mexican Patients with Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) causes memory deficit and alterations in other cognitive functions, mainly in adults over 60 years of age. As the diagnosis confirmation is performed by a postmortem neuropathological examination of the brain, this disease can be confused with other types of dementia at early stages. About 860,000 Mexicans are affected by dementia, most of them with insufficient access to adequate comprehensive health care services. Plasma biomarkers could be a rapid option for early diagnosis of the disease. OBJECTIVE: This study aimed to analyze some plasma biomarkers (amyloid-ß, tau, and lipids) in Mexican AD patients and control subjects with no associated neurodegenerative diseases. METHODS: Plasma amyloid-ß peptides (Aß40 and Aß42), total and phosphorylated tau protein (T-tau and P-tau), and cholesterol and triglyceride levels were quantified by enzyme-linked immunosorbent assay in AD patients and control subjects. RESULTS: In Mexican AD patients, we found significantly lower levels of Aß42 (p < 0.05) compared to the control group. In contrast, significantly higher levels of P-tau (p < 0.05) and triglycerides (p < 0.05) were observed in AD patients compared to controls. Furthermore, a significant correlation was found between the severity of dementia and plasma P-tau levels, Aß42/Aß40 and P-tau/T-tau ratios, and triglycerides concentrations. This correlation increased gradually with cognitive decline. CONCLUSION: The detection of these plasma biomarkers is an initial step in searching for a timely, less invasive, and cost-efficient diagnosis in Mexicans.

Pentylenetetrazol-induced seizures in adult rats are associated with plastic changes to the dendritic spines on hippocampal CA1 pyramidal neurons.

Epilepsy is a chronic neurobehavioral disorder whereby an imbalance between neurochemical excitation and inhibition at the synaptic level provokes seizures. Various experimental models have been used to study epilepsy, including that based on acute or chronic administration of Pentylenetetrazol (PTZ). In this study, a single PTZ dose (60 mg/kg) was administered to adult male rats and 30 min later, various neurobiological parameters were studied related to the transmission and modulation of excitatory impulses in pyramidal neurons of the hippocampal CA1 field. Rats experienced generalized seizures 1-3 min after PTZ administration, accompanied by elevated levels of Synaptophysin and Glutaminase. This response suggests presynaptic glutamate release is exacerbated to toxic levels, which eventually provokes neuronal death as witnessed by the higher levels of Caspase-3, TUNEL and GFAP. Similarly, the increase in PSD-95 suggests that viable dendritic spines are functional. Indeed, the increase in stubby and wide spines is likely related to de novo spinogenesis, and the regulation of neuronal excitability, which could represent a plastic response to the synaptic over-excitation. Furthermore, the increase in mushroom spines could be associated with the storage of cognitive information and the potentiation of thin spines until they are transformed into mushroom spines. However, the reduction in BDNF suggests that the activity of these spines would be down-regulated, may in part be responsible for the cognitive decline related to hippocampal function in patients with epilepsy.

Characterization of the antiapoptotic effect of copper sulfate on striatal and midbrain damage induced by MPP+ in rats.

1-Methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity produces cellular damage resembling that encountered in Parkinson's disease. The mechanisms of cellular death after MPP+ include the participation of oxidative stress in the loss of dopaminergic neurons. Among the mechanisms of defense against oxidative stress, several copper-dependent proteins have been implicated: Cu/Zn-SOD, ceruloplasmin, and metallothionein. Another important mechanism of damage, is MPP + interference with mitochondrial respiration. Both, oxidative stress and inhibition of mitochondrial respiration may trigger apoptosis in the neurons after MPP+. The aim of the present study was to characterize the time-course of apoptosis induced by MPP+ to determine if copper sulfate pretreatment is able to prevent the activation of caspases and decreased the neuronal apoptosis. MPP+ was microinjected into rat striatum using a stereotactic frame. The results showed increased activities of caspases 8, 9 and 3, between 72-120 hours after administration of MPP+, both in striatum and midbrain. After this study, we tested the effect of CuSO4 on MPP+ neurotoxicity, showing a diminution of the apoptotic damage induced by MPP+, decreased levels of enzymatic activity of caspases: 8 (-34 and -25 %), 9 (-25 and -42 %) and 3 (-40 and -29 %) in striatum and midbrain, respectively. Finally, we performed an immunohistochemical analysis, evidencing a decreased number of apoptotic cells in the groups pretreated with copper sulfate pretreatment compared to the control group. With these findings, it is concluded that pretreatment with copper sulfate may be a good alternative to prevent MPP+-induced apoptosis.

Noninvasive transcranial focal stimulation affects the convulsive seizure-induced P-glycoprotein expression and function in rats.

Transcranial focal stimulation (TFS) is a noninvasive neuromodulation strategy that reduces seizure activity in different experimental models. Nevertheless, there is no information about the effects of TFS in the drug-resistant phenotype associated with P-glycoprotein (Pgp) overexpression. The present study focused on determining the effects of TFS on Pgp expression after an acute seizure induced by 3-mercaptopropionic acid (MPA). P-glycoprotein expression was analyzed by western blot in the cerebral cortex and hippocampus of rats receiving 5 min of TFS (300 Hz, 50 mA, 200 µs, biphasic charge-balanced squared pulses) using a tripolar concentric ring electrode (TCRE) prior to administration of a single dose of MPA. An acute administration of MPA induced Pgp overexpression in cortex (68 ±â€¯13.4%, p < 0.05 vs the control group) and hippocampus (48.5 ±â€¯14%, p < 0.05, vs the control group). This effect was avoided when TFS was applied prior to MPA. We also investigated if TFS augments the effects of phenytoin in an experimental model of drug-resistant seizures induced by repetitive MPA administration. Animals with MPA-induced drug-resistant seizures received TFS alone or associated with phenytoin (75 mg/kg, i.p.). TFS alone did not modify the expression of the drug-resistant seizures. However, TFS combined with phenytoin reduced seizure intensity, an effect associated with a lower prevalence of major seizures (50%, p = 0.03 vs phenytoin alone). Our experiments demonstrated that TFS avoids the Pgp overexpression induced after an acute convulsive seizure. In addition, TFS augments the phenytoin effects in an experimental model of drug-resistant seizures. According with these results, it is indicated that TFS may represent a new neuromodulatory strategy to revert the drug-resistant phenotype.

Propylparaben Reduces the Long-Term Consequences in Hippocampus Induced by Traumatic Brain Injury in Rats: Its Implications as Therapeutic Strategy to Prevent Neurodegenerative Diseases.

BACKGROUND: Severe traumatic brain injury (TBI), an important risk factor for Alzheimer's disease, induces long-term hippocampal damage and hyperexcitability. On the other hand, studies support that propylparaben (PPB) induces hippocampal neuroprotection in neurodegenerative diseases. OBJECTIVE: Experiments were designed to evaluate the effects of subchronic treatment with PPB on TBI-induced changes in the hippocampus of rats. METHODS: Severe TBI was induced using the lateral fluid percussion model. Subsequently, rats received subchronic administration with PPB (178 mg/kg, TBI+PPB) or vehicle (TBI+PEG) daily for 5 days. The following changes were examined during the experimental procedure: sensorimotor dysfunction, changes in hippocampal excitability, as well as neuronal damage and volume. RESULTS: TBI+PEG group showed sensorimotor dysfunction (p < 0.001), hyperexcitability (64.2%, p < 0.001), and low neuronal preservation ipsi- and contralateral to the trauma. Magnetic resonance imaging (MRI) analysis revealed lower volume (17.2%; p < 0.01) and great damage to the ipsilateral hippocampus. TBI+PPB group showed sensorimotor dysfunction that was partially reversed 30 days after trauma. This group showed hippocampal excitability and neuronal preservation similar to the control group. However, MRI analysis revealed lower hippocampal volume (p < 0.05) when compared with the control group. CONCLUSION: The present study confirms that post-TBI subchronic administration with PPB reduces the long-term consequences of trauma in the hippocampus. Implications of PPB as a neuroprotective strategy to prevent the development of Alzheimer's disease as consequence of TBI are discussed.

Continuous Visual Focal Status Epilepticus as the Primary Presentation of NMDA-R and GAD65-R Autoimmune Epilepsy.

Epilepsia partialis continua (EPC) has changed in its clinical and pathophysiological definition throughout time. Several etiologies have been described in addition to classic causes of EPC. The following case depicts a young woman who had a peculiar onset of epilepsy with a continuous visual aura becoming a form of chronic recurrent and non-progressive EPC. The patient was initially misdiagnosed as a non-neurological entity (assumed psychiatric in origin), but finally, an immune-mediated epilepsy was diagnosed, and EEG showed focal status epilepticus during evolution. Once the diagnosis was achieved and immune treatment was established, the patient is seizure free. Early identification of an immune basis in patients with epilepsy is important because immunotherapy can reverse the epileptogenic process and reduce the risk of chronic epilepsy. To date, this is the only case reported with EPC manifesting as a continuous visual aura associated with antiglutamic acid decarboxylase 65 (anti-GAD65) and anti-N-methyl-d-aspartate (anti-NMDA) antibodies.

Decreased serotonin content and release in the ventral hippocampus of prenatally stressed male rats in response to forced swim test.

Prenatal stress modifies the serotonergic system by altering the synthesis, metabolism, receptors and serotonin content in the hippocampus. However, it is currently unknown whether serotonin release in the ventral hippocampus of prenatally stressed rats is altered. In this study, serotonin (5-HT) and its metabolite, 5­hydroxyindoleacetic acid (5-HIAA) levels were analysed in dialysates (in vivo) and in homogenates (in vitro) of the ventral hippocampus. This was made after the sucrose preference test and after forced swim test (FST) in male adult progeny from mothers that were stressed by immersion in cold water during the last week of gestation. Serum concentration of corticosterone was also evaluated in control and in prenatally stressed males. Sucrose preference was differently affected in prenatally stressed males: 69% showed decreased sucrose consumption, and were considered anhedonic; 31% exhibited sucrose consumption similar to control and were considered non­anhedonic. During the FST, increased immobility and decreased swimming were observed in prenatally stressed males. After sucrose test, content and release of 5­HT in prenatally stressed rats were similar to those in the control group, with higher metabolite. After the FST, 5-HT content increased, but its release increased slightly in anhedonic rats and did not change in non-anhedonic rats, with lower metabolite. The response of the adrenal axis to the FST was larger in anhedonic prenatally stressed males, than in control and non­anhedonic males. These data show that behavioural disruption caused by prenatal stress is related to low release and lower metabolism of serotonin in the ventral hippocampus in adult male offspring, as well as to hyperactivity and hyperreactivity of the adrenal axis.

Serotonin and noradrenaline content and release in the dorsal hippocampus during learning and spatial memory in prenatally stressed rats.

Prenatal stress causes learning and spatial memory deficits in adulthood by modifying hippocampal function. The dorsal hippocampus contains serotonergic and noradrenergic neuron terminals, which are related to cognitive processes. It is currently unknown whether prenatal stress modifies serotonin (5-HT) and noradrenaline (NA) content and their release in the hippocampus during cognitive performance. Therefore, we measured these variables in the dorsal hippocampus of prenatally stressed males during spatial learning and memory tests. Cognitive tests were performed in 3-month-old control and prenatally stressed male rats in the Morris Water Maze (MWM). After cognitive tests, the dorsal hippocampus was dissected to quantify 5-HT and NA content. In other males, 5-HT and NA release in the dorsal hippocampus was assessed by microdialysis, before and after cognitive tests. Prenatally stressed males showed longer latencies to reach the platform, compared to control animals. Hippocampal 5-HT content decreased during learning and memory tasks in both groups, while NA content was not modified in prenatally stressed males neither before, nor after learning and memory tests. 5-HT and NA release were significantly lower in prenatally stressed animals during spatial learning and memory tasks. Corticosterone response was greater in prenatally stressed animals compared to controls. These results show that cognitive disruption caused by prenatal stress is related to decreased 5-HT and NA release, and to higher adrenal axis response in prenatally stressed animals.

Sodium Cromoglycate Decreases Sensorimotor Impairment and Hippocampal Alterations Induced by Severe Traumatic Brain Injury in Rats.

Severe traumatic brain injury (TBI) results in significant functional disturbances in the hippocampus. Studies support that sodium cromoglycate (CG) induces neuroprotective effects. This study focused on investigating the effects of post-TBI subchronic administration of CG on hippocampal hyperexcitability and damage as well as on sensorimotor impairment in rats. In contrast to the control group (Sham+SS group), animals undergoing severe TBI (TBI+SS group) showed sensorimotor dysfunction over the experimental post-TBI period (day 2, 55%, p < 0.001; day 23, 39.5%, p < 0.001; day 30, 38.6%, p < 0.01). On day 30 post-TBI, TBI+SS group showed neuronal hyperexcitability (63.3%, p < 0.01). The hippocampus ipsilateral to the injury showed volume reduction (14.4%, p < 0.001) with a volume of damage of 0.15 ± 0.09 mm3. These changes were associated with neuronal loss in the dentate gyrus (ipsilateral, 33%, p < 0.05); hilus (ipsilateral, 77%, p < 0.001; contralateral, 51%, p < 0.001); Cornu Ammonis (CA)1 (ipsilateral, 40%, p < 0.01), and CA3 (ipsilateral, 52%, p < 0.001; contralateral, 34%, p < 0.01). Animals receiving subchronic treatment with CG (50 mg/kg, s.c. daily for 10 days) after TBI (TBI+CG group) displayed a sensorimotor dysfunction less evident than that of the TBI+SS group (p < 0.001). Their hippocampal excitability was similar to that of the Sham+SS group (p = 0.21). The TBI+CG group presented hippocampal volume reduction (12.7%, p = 0.94) and damage (0.10 ± 0.03 mm3, p > 0.99) similar to the TBI+SS group. However, their hippocampal neuronal preservation was similar to that of the Sham+SS group. These results indicate that CG represents an appropriate and novel pharmacological strategy to reduce the long-term sensorimotor impairment and hippocampal damage and hyperexcitability that result as consequences of severe TBI.

Magnolia officinalis Reduces Inflammation and Damage Induced by Recurrent Status Epilepticus in Immature Rats.

BACKGROUND: Neuroinflammation induced in response to damage caused by status epilepticus (SE) activates the interleukin (IL)1-ß pathway and proinflammatory proteins that increase vulnerability to the development of spontaneous seizure activity and/or epilepsy. OBJECTIVES: The study aimed to assess the short-term anti-inflammatory and neuroprotective effects of Magnolia officinalis (MO) on recurrent SE in immature rats. METHODS: Sprague-Dawley rats at PN day 10 were used; n = 60 rats were divided into two control groups, SHAM and KA, and two experimental groups, MO (KA-MO) and Celecoxib (KA-Clbx). The anti-inflammatory effect of a single dose of MO was evaluated at 6 and 24 hr by Western blotting and on day 30 PN via a subchronic administration of MO to assess neuronal preservation and hippocampal gliosis by immunohistochemistry for NeunN and GFAP, respectively. RESULTS: KA-MO caused a decrease in the expression of IL1-ß and Cox-2 at 6 and 24 h post-treatment, a reduction in iNOS synthase at 6 and 24 hr post-treatment and reduced neuronal loss and gliosis at postnatal day 30, similar to Clbx. CONCLUSION: The results indicating that Magnolia officinalis is an alternative preventive treatment for early stages of epileptogenesis are encouraging.

Single vs. Combined Therapeutic Approaches in Rats With Chronic Spinal Cord Injury.

The regenerative capability of the central nervous system is limited after traumatic spinal cord injury (SCI) due to intrinsic and extrinsic factors that inhibit spinal cord regeneration, resulting in deficient functional recovery. It has been shown that strategies, such as pre-degenerated peripheral nerve (PPN) grafts or the use of bone marrow stromal cells (BMSCs) or exogenous molecules, such as chondroitinase ABC (ChABC) promote axonal growth and remyelination, resulting in an improvement in locomotor function. These treatments have been primarily assessed in acute injury models. The aim of the present study is to evaluate the ability of several single and combined treatments in order to modify the course of chronic complete SCI in rats. A complete cord transection was performed at the T9 level. One month later, animals were divided into five groups: original injury only (control group), and original injury plus spinal cord re-transection to create a gap to accommodate BMSCs, PPN, PPN + BMSCs, and PPN + BMSCs + ChABC. In comparison with control and single-treatment groups (PPN and BMSCs), combined treatment groups (PPN + BMSCs and PPN + BMSCs + ChABC) showed significative axonal regrowth, as revealed by an increase in GAP-43 and MAP-1B expression in axonal fibers, which correlated with an improvement in locomotor function. In conclusion, the combined therapies tested here improve locomotor function by enhancing axonal regeneration in rats with chronic SCI. Further studies are warranted to refine this promising line of research for clinical purposes.