Animal Models Of Brain Injury Research Articles

N-3 Polyunsaturated fatty acids in animal models with neuroinflammation

Neuroinflammation is present in the majority of acute and chronic neurological disorders. Excess or prolonged inflammation in the brain is thought to exacerbate neuronal damage and loss. Identifying modulators of neuroinflammation is an active area of study since it may lead to novel therapies. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are anti-inflammatory in many non-neural tissues; their role in neuroinflammation is less studied. This review summarizes the relationship between n-3 PUFA and brain inflammation in animal models of brain injury and aging. Evidence by and large shows protective effects of n-3 PUFA in models of sickness behavior, stroke, aging, depression, Parkinson's disease, diabetes, and cytokine- and irradiation-induced cognitive impairments. However, rigorous studies that test the direct effects of n-3 PUFA in neuroinflammation in vivo are lacking. Future research in this area is necessary to determine if, and if so which, n-3 PUFA directly target brain inflammatory pathways. n-3 PUFA bioactive metabolites may provide novel therapeutic targets for neurological disorders with a neuroinflammatory component.

Unmasking Sex-Based Disparity in Neuronal Metabolism

Both classic and emerging literature point to sex-based disparity in neuronal metabolism. While detectable under baseline conditions, this phenomenon appears to be exaggerated or sometimes unmasked in neurons by cellular stress. A complex sex-dependent response to nutrient deprivation, excitotoxicity, oxidative/nitrositive stress, oxygen-glucose deprivation, and chemical toxicity has been observed in neurons in vitro, as well as after various insults including ischemic or traumatic brain injury in vivo. Importantly, sex-based disparity in response to diverse therapeutics has been seen in neurons in culture, contemporary animal models of brain injury, and in human disease. These have clear implications for pharmacological design of therapeutics targeting central nervous system diseases involving both males and females, and preclinical testing of promising agents.

Effect of maternal administration of allopregnanolone before birth asphyxia on neonatal hippocampal function in the spiny mouse

Clinically, treatment options where fetal distress is anticipated or identified are limited. Allopregnanolone is an endogenous steroid, that positively modulates the GABA A receptor, and that has anti-apoptotic and anti-excitotoxic actions, reducing brain damage in adult animal models of brain injury. We sought to determine if prophylactic treatment of the pregnant female with a single dose of this steroid could reduce birth asphyxia-induced losses in hippocampal function at 5 days of age (P5) in spiny mouse neonates ( Acomys cahirinus). At 37 days gestation (term = 39 days) and 1 h before inducing birth asphyxia, spiny mice dams were injected subcutaneously (0.2 ml) with either 3 mg/kg allopregnanolone or 20% w/v β-cyclodextrin vehicle. One hour later, fetuses were either delivered immediately by caesarean section (control group) or exposed to 7.5 min of in utero asphyxia, causing acidosis and hypoxia. At P5, ex vivo hippocampal plasticity was assessed, or brains collected to determine cell proliferation (proliferating cell nuclear antigen; PCNA) or calcium channel expression (inositol trisphosphate receptor type 1; IP 3R1) using immunohistochemistry. Allopregnanolone partially prevented the decrease in long term potentiation at P5, and the asphyxia-induced increase in IP 3R1 expression in CA1 pyramidal neurons. There was no effect of allopregnanolone on the asphyxia induced impairment of the input/output (I/O) curve and paired-pulse facilitation (PPF). In control birth pups, maternal allopregnanolone treatment caused significant changes in short term post-synaptic plasticity and also reduced hippocampal proliferation at P5. These findings show that allopregnanolone can modulate hippocampal development and synaptic function in a normoxic or hypoxic environment, possibly by modifying calcium metabolism. Best practice for treatment dose and timing of treatment will need to be carefully considered.

Biomarkers of Developmental Brain Injury in Preterm Infants: Reporting on Metabolomics Activities of the Neobrain Consortium

Background and aims: A novel component in the Neobrain consortium was the large scale quantification of metabolites and their implication/use for translational research. Here we report on the 1) adequacy of the metabolomics technology 2) characterisation of metabolic responses to several types of injury in plasma 3) identification of metabolic markers of brain injury in animal models and humans. Methods: Study comprises animal models of hypoxia-ischemia, excitotoxic brain injury and intrauterine LPS exposure in fetal sheep and a human cohort of 41 preterm infants (28-32 weeks of gestation). Metabolite panel covering 230 compounds (acylcarnitines, lipids, prostanoids, amino acids and derivatives, oxidised products of cholesterol, small organic acids,sugars) was applied in plasma. In the sheep model and infants, extend of brain damage has been assessed by MRI, aEEG and histopathology in animals.Results: Insults causing brain injury induced significant changes in the plasma metabolome in all animal models. In the sheep model we detected a significant correlation of metabolites with outcome at several time points. In the preterm infants ADMA/SDMA, specific acyl carnitines, lysoPCs and amino acids were significantly increased in infants with abnormal MRI at term, overlapping with metabolites detected in the animal models.Conclusions: Hypothesized at the start at the project, metabolic changes associated with perinatal brain injury is demonstrated in several animal models and translated in humans. Metabolite profiling can effectively be applied to pediatric research to complete our fragmented knowledge. It enables identification of patterns of dysregulation (biomarker discovery) together with the elucidation of their underlying mechanism (biological plausibility).

Brain-systemic temperature gradient is temperature-dependent in children with severe traumatic brain injury

To understand the gradient between rectal and brain temperature in children after severe traumatic brain injury. We hypothesized that the rectal temperature and brain temperature gradient will be influenced by the child's body surface area and that this relationship will persist over physiologic temperature ranges. Retrospective review of a prospectively collected pediatric neurotrauma registry. Academic, university-based pediatric neurotrauma program. Consecutive children (n = 40) with severe traumatic brain injury (Glasgow coma scale of <8) who underwent brain temperature monitoring (July 2003 to December 2008) were studied after informed consent was obtained. A subset of children (n = 24) were concurrently enrolled in a randomized, controlled clinical trial of early-moderate hypothermia for neuroprotection. Data extraction of multiple clinical variables, including demographic data, body surface area, and rectal and brain temperature at recorded at hourly intervals. Paired brain and rectal temperature measurements (in degrees Celsius, n = 4369) were collected hourly and compared by using Pearson correlations. Patients were stratified according to body surface area (<1.0 m, 1.0-1.99 m, 2.0-2.99 m, and >3.0 m) and based on brain temperature (≤34.0, 34.1-36.0; 36.1-38, ≥38.1). Body surface area and brain temperature were compared between groups by using Pearson correlations with correction for repeated measures. Mean brain temperature-rectal temperature difference was calculated for stratified brain temperature ranges. Overall, brain and rectal temperatures were highly correlated (r = .86, p < .001). During brain hyperthermia, brain temperature-rectal temperature was similar to that reported in previous studies with brain temperature higher than rectal temperature (1.75 ± 0.4; r = .54). Surprisingly, this relationship was reversed during brain hypothermia (brain temperature-rectal temperature = -1.87 ± 0.8; r = .37), indicating a reversal of the brain-systemic temperature gradient. When stratified for body surface area, the correlation between rectal temperature and brain temperature remained strong (r = .78, 0.91, 0.79 and 0.95, respectively, p < .001). However, the correlation between brain temperature and rectal temperature was substantially decreased when stratified for brain temperature (r = .37, 0.58, 0.48, 0.54, p < .001). In particular, during moderate brain hypothermia (brain temperature ≤34), the correlation between brain temperature and rectal temperature was weakest, indicating the greatest variability during this condition which is often targeted for therapeutic trials. Brain temperature and rectal temperature are generally well-correlated in children with traumatic brain injury. This relationship is different at the extremes of the physiologic temperature range, with the temperature gradient reversed during brain hypothermia and hyperthermia. Given that studies showing neuroprotection from hypothermia in animal models of brain injury generally target brain temperature, our data suggest the possibility that, if brain temperature were the therapeutic target in clinical trials, this would result in somewhat higher systemic temperature and potentially fewer side effects. This relationship may be exploited in future clinical trials to maintain brain hypothermia (for neurologic protection) at slightly higher systemic temperatures (and potentially fewer systemic side effects).

Nerve Growth Factor and Human Umbilical Cord Blood-Derived Cells Confer Neurovascular Protection in Ischemia

Human umbilical cord blood (HUCB), a valuable source for cell therapy of hematologic diseases, was recently found to confer neuroprotection in animal models of brain injury. To explore the neuroprotective properties of HUCB in an ischemic environment, we studied a unique sub-population of collagen-adherent cells. In the presence of nerve growth factor (NGF) and interferon-gamma, these cells differentiate in vitro into a neuronal phenotype (termed HUCBNPs). Using a closed-head injury brain trauma model, we recently demonstrated neuroprotective effects of HUCB upon their local injection into the brain. Our in-vitro studies indicated that upon co-culture with ischemia exposed PC12 cells, HUCBNP conferred about 30% neuroprotection, as assessed by decreased lactate dehydrogenase (LDH) release and inhibition of caspase-3 activity. HUCBNP decreased by 95% the level of free radicals in the insulted-PC12 cells, which was in correlation with the appearance of antioxidants and NGF in the medium. HUCBNP-induced neuroprotection also correlated with changes in NGF mRNA expression levels, a process which was blocked by K252a, an antagonist of the NGF-neurotrophin receptor TrkA. To further extend the possible contribution of NGF-mediated protective role, we investigated its neuroprotective mechanisms using PC12 cells and brain capillary endothelial cells exposed to ischemic insult. Pretreatment of the cultures with NGF conferred neuroprotection in a dose- and time-dependent fashion. Time course experiments indicated marked activation of mitogen activated protein kinasas (MAPKs) during the ischemic insult, while treatment of the cultures with NGF inhibited them to different degrees. It appears that both neuronal and endothelial compartments may be protected by NGF under ischemic conditions. Therefore, in future neuroprotection studies, we propose to address additional components of the neurovascular unit such as astrocytes and pericytes in mono-, co- and multi-culture setups. In conclusion, our findings indicate that HUCBNP-induced neuroprotection involves antioxidant(s) and NGF, which by paracrine and/or autocrine route, affects all components of the neurovascular unit.

Spreading depolarizations have prolonged direct current shifts and are associated with poor outcome in brain trauma

Cortical spreading depolarizations occur spontaneously after ischaemic, haemorrhagic and traumatic brain injury. Their effects vary spatially and temporally as graded phenomena, from infarction to complete recovery, and are reflected in the duration of depolarization measured by the negative direct current shift of electrocorticographic recordings. In the focal ischaemic penumbra, peri-infarct depolarizations have prolonged direct current shifts and cause progressive recruitment of the penumbra into the core infarct. In traumatic brain injury, the effects of spreading depolarizations are unknown, although prolonged events have not been observed in animal models. To determine whether detrimental penumbral-type depolarizations occur in human brain trauma, we analysed electrocorticographic recordings obtained by subdural electrode-strip monitoring during intensive care. Of 53 patients studied, 10 exhibited spreading depolarizations in an electrophysiologic penumbra (i.e. isoelectric cortex with no spontaneous activity). All 10 patients (100%) with isoelectric spreading depolarizations had poor outcomes, defined as death, vegetative state, or severe disability at 6 months. In contrast, poor outcomes were observed in 60% of patients (12/20) who had spreading depolarizations with depression of spontaneous activity and only 26% of patients (6/23) who had no depolarizations (χ2, P<0.001). Spontaneous electrocorticographic activity and direct current shifts of depolarizations were further examined in nine patients. Direct current shift durations (n=295) were distributed with a significant positive skew (range 0:51-16:19 min:s), evidencing a normally distributed group of short events and a sub-group of prolonged events. Prolonged direct current shifts were more commonly associated with isoelectric depolarizations (median 2 min 36 s), whereas shorter depolarizations occurred with depression of spontaneous activity (median 2 min 10 s; P<0.001). In the latter group, direct current shift durations correlated with electrocorticographic depression periods, and were longer when preceded by periodic epileptiform discharges than by continuous delta (0.5-4.0 Hz) or higher frequency activity. Prolonged direct current shifts (>3 min) also occurred mainly within temporal clusters of events. Our results show for the first time that spreading depolarizations are associated with worse clinical outcome after traumatic brain injury. Furthermore, based on animal models of brain injury, the prolonged durations of depolarizations raise the possibility that these events may contribute to maturation of cortical lesions. Prolonged depolarizations, measured by negative direct current shifts, were associated with (i) isoelectricity or periodic epileptiform discharges; (ii) prolonged depression of spontaneous activity and (iii) occurrence in temporal clusters. Depolarizations with these characteristics are likely to reflect a worse prognosis.

Cerebral metabolism after forced or voluntary physical exercise

The pathophysiology of stroke, a leading cause of morbidity and mortality, is still in the process of being understood. Pre-ischemic exercise has been known to be beneficial in reducing the severity of stroke-induced brain injury in animal models. Forced exercise with a stressful component, rather than voluntary exercise, was better able to induce neuroprotection. This study further determined the changes in cerebral metabolism resulting from the two methods of exercise (forced versus voluntary).Adult male Sprague–Dawley rats were randomly assigned to 3 groups: the control group (no exercise), the forced treadmill exercise group, and the voluntary running wheel exercise group. In order to measure the extent of cerebral metabolism in animals with different exercise regimens, mRNA levels and protein expression of glucose transporter 1 and glucose transporter 3 (GLUT-1 and GLUT-3), phosphofructokinase (PFK), lactate dehydrogenase (LDH), and adenosine monophosphate kinase (AMPK) were measured utilizing real-time reverse transcription polymerase chain reaction (PCR) analysis as well as Western blot analysis. Phosphorylated AMPK activity was also measured using an ELISA activity kit, and hypoxic inducible factor (HIF)-1α was measured at transcription and translation levels.The data show that the forced exercise group had a significant (p < 0.05) increase in cerebral glycolysis, including expressions of GLUT-1, GLUT-3, PFK, LDH, phosphorylated AMPK activity and HIF-1α, when compared to the voluntary exercise and the control groups. Our results suggest that the effects of different exercise on HIF-1α expression and cerebral glycolysis may provide a possible reason for the discrepancy in neuroprotection, with forced exercise faring better than voluntary exercise through increased cerebral metabolism.

Lesões cerebrais agudas e sua influência sobre a motilidade gastrintestinal

Subarachnoid hemorrhage can increase intracranial pressure, causing significant morbidity. Acute gastric dilation and delayed gastric emptying are commonly seen in patients with intracranial hypertension, and correction of these gastric abnormalities can facilitate the recovery of patients with brain injuries. We conducted a literature review of both national and international health sciences medical journals and electronic libraries spanning the last twenty-eight years and focused on the brain, gut motility and gastric emptying functional axis either in experimental animal models of brain injury or patients with acute cerebral injuries. Decreased parasympathetic tonus is a potential cause of intracranial hypertension-related food intolerance. Changes in gastrointestinal transit after a brain injury follow a biphasic pattern: an initial phase of accelerated gastric emptying and a late stage of intestinal lethargy. Changes in the physiology underlying gut motility may be essential for homeostatic stabilization in hemodynamically unstable patients. Research studies are necessary to understand the difficult management of intensive care patients with intracranial hypertension secondary to subarachnoid hemorrhages resulting from traumatic brain injuries or rupture of a cerebral aneurysm. Increased intracranial pressure induces massive increases in sympathetic activity, which is responsible for many of the peripheral systemic and gastrointestinal symptoms. Brain injuries leading to significant increases in intracranial pressure result in delayed gastrointestinal emptying due to autonomic nervous system changes.

The Neuroprotective Effects of 6-cyano-7-nitroquinoxalin-2,3-dione (CNQX) Via Mediation of Nitric Oxide Synthase on Hypoxic-ischemic Brain Injury in Neonatal Rats

Purpose: Current studies have demonstrated the neuroprotective effects of 6-cyano-7-nitroquinoxalin-2,3-dione (CNQX) in many animal models of brain injury, including hypoxic-ischemic (HI) encephlopathy, trauma and excitotoxicity, but limited data are available for those during the neonatal periods. Here we investigated whether CNQX can protect the developing rat brain from HI injury via mediation of nitric oxide synthase. Methods: In an in vivo model, left carotid artery ligation was done in 7-day-old Sprague-Dawley (SD) rat pups. The animals were divided into six groups; normoxia (N), hypoxia (H), hypoxia with sham-operation (HS), hypoxia with operation (HO), HO treated with vehicle (HV), and HO treated with CNQX at a dose of 10 mg/kg (HC). Hypoxia was made by exposure to a 2 hr period in the hypoxic chamber (92% N2, 8% O2). In an in vitro model, embryonic cortical neuronal cell culture of SD rats at 18-day gestation was done. The cultured cells were divided into three groups: normoxia (N), hypoxia (H), and hypoxia treated with CNQX (HC). The N group was prepared in 5% CO2 incubators and the other groups were placed in 1% O2 incubators (94% N2, 5% CO2) for 16 hr. Results: In the in vitvo and in vivo models, the expressions of iNOS and eNOS were reduced in the hypoxia group when compared to the normoxia group, whereas they were increased in the CNQX-treated group compared to the hypoxia group. In contrast, the expression of nNOS was showed reversely. Conclusion: CNQX has neuroprotective property over perinatal HI brain injury via mediation of nitric oxide synthase.

Is Neuronal Death Necessary for Acquired Epileptogenesis in the Immature Brain?

A central question concerning acquired epileptogenesis in the immature brain is whether neuronal death is required for the development of epilepsy after a brain insult. Results from three different animal models of brain injury during early development have been used to develop the hypothesis that status epilepticus, prolonged febrile seizures, or hypoxia-induced seizures can lead to chronic epilepsy without the occurrence of neuronal death. This brief review will summarize the evidence supporting the hypothesis in each model and then critique the data and published interpretations. A case will be made that the evidence to date neither rules out the occurrence of neuronal death nor demonstrates that epileptogenesis (i.e., spontaneous recurrent seizures) has actually occurred in these animal models of acquired pediatric epilepsy. We also review evidence for the opposing hypothesis: acquired epileptogenesis in the immature brain requires, or at least often involves, neuronal death.

Mechanisms and pathophysiology of the low-level blast brain injury in animal models

The symptoms of primary blast-induced mTBI, posttraumatic stress disorder and depression overlap. Evidence of an organic basis for these entities has been scarce and controversial. We present a review of animal studies demonstrating that low-level blast causes pathophysiological and functional changes in the brain. We monitor a time period from minutes to approximately 1 week after blast exposure from multiple modes (air, underwater, localized and whole body). The most salient findings observed were (1) the peak pressures ( P max) in the brain, elicited from the blast from the firing of military weapons ( P max 23–45 kPa), have a similar magnitude as that registered in air close to the head. Corresponding measurements during the detonation pulse from explosives under water show a P max in the brain, which is only 10% of that in water outside the head. (2) The rise time of the pressure curve is 10 times longer in the brain as compared with the blast in air outside the head during firing of military weapons. (3) The lower frequencies in the blast wave appear to be transmitted more readily to the brain than the higher frequencies. (4) When animals are exposed to low levels of blast, the blast wave appears mostly transmitted directly to the brain during air exposure, not via the thorax or abdomen. (5) Low levels of blast cause brain edema, as indicated by increased bioelectrical impedance, an increase in the intracranial pressure, small brain hemorrhages and impaired cognitive function.

The comparison of mouse full metallothionein‐1 versus α and β domains and metallothionein‐1‐to‐3 mutation following traumatic brain injury reveals different biological motifs

Traumatic injury to the brain is one of the leading causes of injury-related death or disability, but current therapies are limited. Previously it has been shown that the antioxidant proteins metallothioneins (MTs) are potent neuroprotective factors in animal models of brain injury. The exogenous administration of MTs causes effects consistent with the roles proposed from studies in knock-out mice. We herewith report the results comparing full mouse MT-1 with the independent alpha and beta domains, alone or together, in a cryoinjury model. The lesion of the cortex caused the mice to perform worse in the horizontal ladder beam and the rota-rod tests; all the proteins showed a modest effect in the former test, while only full MT-1 improved the performance of animals in the rota-rod, and the alpha domain showed a rather detrimental effect. Gene expression analysis by RNA protection assay demonstrated that all proteins may alter the expression of host-response genes such as GFAP, Mac1 and ICAM, in some cases being the beta domain more effective than the alpha domain or even the full MT-1. A MT-1-to-MT-3 mutation blunted some but not all the effects caused by the normal MT-1, and in some cases increased its potency. Thus, splitting the two MT-1 domains do not seem to eliminate all MT functions but certainly modifies them, and different motifs seem to be present in the protein underlying such functions.

Is There a Place for Cerebral Preconditioning in the Clinic?

Preconditioning (PC) describes a phenomenon whereby a sub-injury inducing stress can protect against a later injurious stress. Great strides have been made in identifying the mechanisms of PC-induced protection in animal models of brain injury. While these may help elucidate potential therapeutic targets, there are questions over the clinical utility of cerebral PC, primarily because of questions over the need to give the PC stimulus prior to the injury, narrow therapeutic windows and safety. The object of this review is to address the question of whether there may indeed be a clinical use for cerebral PC and to discuss the deficiencies in our knowledge of PC that may hamper such clinical translation.

The neuroprotective effect of recombinant human erythropoietin via an antiapoptotic mechanism on hypoxic-ischemic brain injury in neonatal rats

PurposeThe neuroprotective effects of erythropoietin (EPO) have been recently shown in many animal models of brain injury, including hypoxic-ischemic (HI) encephalopathy, trauma, and excitotoxicity; however, limited data are available for such effects during the neonatal periods. Therefore, we investigated whether recombinant human EPO (rHuEPO) can protect against perinatal HI brain injury via an antiapoptotic mechanism.MethodsThe left carotid artery was ligated in 7-day-old Sprague-Dawley (SD) rat pups (in vivo model). The animals were divided into 6 groups: normoxia control (NC), normoxia sham-operated (NS), hypoxia only (H), hypoxia+vehicle (HV), hypoxia+rHuEPO before a hypoxic insult (HE-B), and hypoxia+rHuEPO after a hypoxic insult (HE-A). Embryonic cortical neuronal cell culture of SD rats at 18 days gestation (in vitro model) was performed. The cultured cells were divided into 5 groups: normoxia (N), hypoxia (H), and 1, 10, and 100 IU/mL rHuEPO-treated groups.ResultsIn the in vivo model, Bcl-2 expressions in the H and HV groups were lower than those in the NC and NS groups, whereas those in the HE-A and HE-B groups were greater than those of the H and HV groups. The expressions of Bax and caspase-3 and the ratio of Bax/Bcl-2 were in contrast to those of Bcl-2. In the in vitro model, the patterns of Bcl-2, Bax, and caspase-3 expression and Bax/Bcl-2 ratio were similar to the results obtained in the in vivo model.ConclusionrHuEPO exerts neuroprotective effect against perinatal HI brain injury via an antiapoptotic mechanism.

Concussion in Professional Football: Animal Model of Brain Injury—Part 15

Concussion in Professional Football: Animal Model of Brain Injury—Part 15

Combined 17β‐Oestradiol and Progesterone Treatment Prevents Neuronal Cell Injury in Cortical but not Midbrain Neurones or Neuroblastoma Cells

Oestrogens are powerful endogenous and exogenous neuroprotective hormones in animal models of brain injury, including focal cerebral ischaemia. This protective effect has been demonstrated under a variety of different treatments and injury paradigms, such as in vivo and in vitro stroke conditions. Neuroprotection in the central nervous system by progesterone is less defined. In the present study, cultured cortical and midbrain mouse neurones and human neuroblastoma cells (SH-SY5Y) were exposed to combined glucose-serum deprivation (CGSD), which is regarded as a reliable model mimicking the effects of ischaemia in vitro. Cell viability was assayed using lactate dehydrogenase release and metabolic activity. Conditions for CGSD treatment were chosen to yield half-maximal cell death rates. The validity of CGSD in vitro was compared with permanent middle cerebral artery occlusion (MCAO) in vivo. CGSD for 4 h induced half-maximal neuronal cell death. MCAO in vivo for the same period resulted in significant neuronal loss, also suggesting the validity of CGSD as a suitable stroke-like in vitro model. Combined steroid treatment (17beta-oestradiol and progesterone) but not the application of single steroids abolished CGSD-induced cell death of cortical neurones in vitro. By contrast, no cell protection was found in midbrain neurones or neuroblastoma cells. The co-application of oestrogen (ICI 182,780) or progesterone (RU-486) receptor antagonists did not obviously counteract the protective steroid effects. This suggests the operation of nonclassical steroid mechanisms and their implication in mediation of hormonal effects. The surplus of combined protective hormonal effects might be a result of the observed influence of progesterone application on neuronal oestradiol synthesis. The data obtained in the present study clearly highlight the potential of a combined steroid treatment under toxic degenerative brain pathologies.

Review of Lithium Effects on Brain and Blood

Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3beta (GSK3 beta). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/beta-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.

2020 Is 18F-FDG a surrogate tracer to measure tumor hypoxia? Comparison with the hypoxic tracer 14C-EF3 in animal tumour models

The pathophysiology of stroke, a leading cause of morbidity and mortality, is still in the process of being understood. Pre-ischemic exercise has been known to be beneficial in reducing the severity of stroke-induced brain injury in animal models. Forced exercise with a stressful component, rather than voluntary exercise, was better able to induce neuroprotection. This study further determined the changes in cerebral metabolism resulting from the two methods of exercise (forced versus voluntary).Adult male Sprague–Dawley rats were randomly assigned to 3 groups: the control group (no exercise), the forced treadmill exercise group, and the voluntary running wheel exercise group. In order to measure the extent of cerebral metabolism in animals with different exercise regimens, mRNA levels and protein expression of glucose transporter 1 and glucose transporter 3 (GLUT-1 and GLUT-3), phosphofructokinase (PFK), lactate dehydrogenase (LDH), and adenosine monophosphate kinase (AMPK) were measured utilizing real-time reverse transcription polymerase chain reaction (PCR) analysis as well as Western blot analysis. Phosphorylated AMPK activity was also measured using an ELISA activity kit, and hypoxic inducible factor (HIF)-1α was measured at transcription and translation levels.The data show that the forced exercise group had a significant (p < 0.05) increase in cerebral glycolysis, including expressions of GLUT-1, GLUT-3, PFK, LDH, phosphorylated AMPK activity and HIF-1α, when compared to the voluntary exercise and the control groups. Our results suggest that the effects of different exercise on HIF-1α expression and cerebral glycolysis may provide a possible reason for the discrepancy in neuroprotection, with forced exercise faring better than voluntary exercise through increased cerebral metabolism.

Effect of naloxone hydrochloride on neuronal cell apoptosis and cerebral edema induced by experimental brain injury

Objective To investigate the effects of naloxone hydrechloride on neuronal cell apoptosis and cerebral edema induced by experimental brain injury.Method Animal model of brain injury was established by free-falling method of Fecney.Totally 100 SD rats were randomly divided into sham operated group(n=20),op-erated comparison group(n=40),and naloxone hydrochloride treatment group(n=40).The naloxone hy-drochloride treatment group were subdivided into four sub-groups,and naloxone hydrochloride was injected at 30 min,6 h,24 h and 48 h after brain injury respectively,while the comparison groups were injected with physiologi-cal saline at the same time point.The rats were sacrificed 7 deys after the injury.Neuronal cell apoptosis were de-tected by terminal-deoxynucleotidyl transferase mediated nick end labeling(TUNEL),and water content of brain tis-sue was examined with dry-wet methods.Data were analyzed by using spss 10.0 saftware package statistical analysis was carried out by using variance analysis.Results Gompared to the sham operated group,neuronal cell apopto-sis and water content of brain tissue were increased significantly in operated comparison group(P＜0.05).Com-pared to the operated comparison group,neuronal cell apoptosis and water content of brain tissue were decreased significantly in every naloxone hydirochloride treatment group(P＜0.05).Every sub-groups compared in naloxone hydrochloride treatment group,neuronal cell apoptosis of early injection group(30 min and 6 h after injury)were decreased significantly than late injection group(24 h and 48 h after injury,P＜0.05),but the water content of brain tissue had no difference between the early injection group and the late injection group(P＞0.05).Conclu-sions Naloxone can carry out its protective function to injuried neurecyte through alleviating neuronal cell apopto-sis and hydrecepahalus.and the effect was better as early as it used. Key words: Naloxone; Brain injury; Hydrocephalus; Apoptosis