Neuroprotection from inflammation: Experimental allergic encephalomyelitis facilitates traumatic spinal cord injury recovery

Passive immunization with T cells activated against central nervous system (CNS) - associated myelin antigens has been found to provide neuroprotection following CNS trauma, leading to the concept of protective autoimmunity. However, limited research exists about whether actively induced CNS autoimmunity may offer any similar benefit. In this study, the kinetics and the effect of endogenously anti-myelin activated T cells following spinal cord injury (SCI), were investigated. Experimental allergic encephalomyelitis (EAE) was actively induced in Lewis rats following immunization with myelin basic protein (MBP). In vivo 5-Bromo-2-deoxyuridine (BrdU) incorporation from activated T cells was used as a marker of T cell- proliferation. BrdU was injected on 5th, 6th and 7th day post-induction (DPI) at all EAE-animals. On DPI 8, spinal cord compressive injury was induced by a transient extradural application of an aneurysm clip at the T8 spinal level. SCI resulted in spastic paralysis of hindlimbs, in all but sham-injured animals. Recovery from SCI was significantly better in EAE-animals. Activated mononuclear cells were selectively accumulated at the site of the injury. Axonal loss was less in the EAE group following SCI. Our findings indicate that actively induced autoimmunity against CNS myelin antigens may protect spinal cord pathways from mechanical injury

Maternal separation prior to neonatal hypoxia-ischemia: Impact on emotional aspects of behavior and markers of synaptic plasticity in hippocampus

Exposure to early-life stress is associated with long-term alterations in brain and behavior, and may aggravate the outcome of neurological insults. This study aimed at investigating the possible interaction between maternal separation, a model of early stress, and subsequent neonatal hypoxia-ischemia on emotional behavior and markers of synaptic plasticity in hippocampus. Therefore, rat pups (N = 60) were maternally separated for a prolonged (MS 180min) or a brief (MS 15min) period during the first six postnatal days, while a control group was left undisturbed. Hypoxia-ischemia was applied to a subgroup of each rearing condition on postnatal day 7. Emotional behavior was examined at three months of age and included assessments of anxiety (elevated plus maze), depression-like behavior (forced swimming) and spontaneous exploration (open field). Synaptic plasticity was evaluated based on BDNF and synaptophysin expression in CA3 and dentate gyrus hippocampal regions. We found that neonatal hypoxia-ischemia caused increased levels of anxiety, depression-like behavior and locomotor activity (ambulation). Higher anxiety levels were also seen in maternally separated rats (MS180min) compared to non-maternally separated rats, but prolonged maternal separation prior to HI did not potentiate the HI-associated effect. No differences among the three rearing conditions were found regarding depression-like behavior or ambulation. Immunohistochemical evaluation of synaptophysin revealed that both prolonged maternal separation (MS180min) and neonatal hypoxia-ischemia significantly reduced its expression in the CA3 and dentate gyrus. Decreases in synaptophysin expression in these areas were not exacerbated in rats that were maternally separated for a prolonged period prior to HI. Regarding BDNF expression, we found a significant decrease in immunoreactivity only in the hypoxic-ischemic rats that were subjected to the prolonged maternal separation paradigm. The above findings suggest that early-life stress prior to neonatal hypoxia-ischemia leads to significant alterations in synaptic plasticity of the dorsal hippocampus during adulthood, but does not exacerbate HI-related changes in emotional behavior

Effects of maternal separation on behavior and brain damage in adult rats exposed to neonatal hypoxia–ischemia

Animal studies suggest that maternal separation, a widely used paradigm to study the effects of early life adversity, exerts a profound and life-long impact on both brain and behavior. The aim of the current study was to investigate whether adverse early life experiences interact with neonatal hypoxia–ischemia, affecting the outcome of this neurological insult at both functional and structural levels during adulthood. Rat pups were separated from their mothers during postnatal days 1–6, for either a short (15 min) or prolonged (180 min) period, while another group was left undisturbed. On postnatal day 7, a subgroup from each of the three postnatal manipulations was exposed to a hypoxic–ischemic episode. Behavioral examination took place approximately at three months of age and included tests of learning and memory (Morris water maze, novel object and novel place recognition), as well as motor coordination (rota-rod). We found that both prolonged maternal separation and neonatal hypoxia–ischemia impaired the animals’ spatial learning and reference memory. Deficits in spatial but not visual recognition memory were detected only in hypoxic–ischemic rats. Interestingly, prolonged maternal separation prior to neonatal hypoxia–ischemia augmented the reference memory impairments. Histological analysis of infarct size, hippocampal area and thickness of corpus callosum did not reveal any exacerbation of damage in hypoxic–ischemic rats that were maternally separated for a prolonged period. These are the first data suggesting that an adverse postnatal environmental manipulation of just 6 days causes long-term effects on spatial learning and memory and may render the organism more vulnerable to a subsequent insult

Effect of angiotensin-converting enzyme tag single nucleotide polymorphisms on the outcome of patients with traumatic brain injury

BackgroundGenetic variants appear to influence, at least to some degree, the extent of brain injury and the clinical outcome of patients who have sustained a traumatic brain injury (TBI). Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase that is implicated in the regulation of blood pressure and cerebral circulation. ACE gene polymorphisms were found to regulate serum ACE enzyme activity.ObjectiveThe present study aimed to investigate possible influence of ACE gene region variants on patients’ outcome after TBI.Patients and methodsIn total, 363 TBI patients prospectively enrolled in the study were genotyped for five tag single nucleotide polymorphisms (SNPs) across the ACE gene. Using logistic regression analyses, tag SNPs and their constructed haplotypes were tested for associations with 6-month Glasgow Outcome Scale scores, after adjustment for age, sex, Glasgow Coma Scale scores at admission, and the presence of a hemorrhagic event in the initial computed tomography scan.ResultsSignificant effects on TBI outcome were found for three neighboring tag SNPs in the codominant (genotypic) model of inheritance [rs4461142: odds ratio (OR) 0.26, 95% confidence interval (CI) 0.12-0.57, P=0.0001; rs7221780: OR 2.67, 95% CI 1.25-5.72, P=0.0003; and rs8066276: OR 3.82, 95% CI 1.80-8.13, P=0.0002; for the heterozygous variants compared with the common alleles]. None of the constructed common tag SNPs haplotypes was associated with TBI outcome.ConclusionThe present study provides evidence of the possible influence of genetic variations in a specific region of the ACE gene on the outcome of TBI patients. This association may have pharmacogenetic implications in identifying those TBI patients who may benefit from ACE inhibition

Argininemia: Pathophysiology and Novel Methods for Evaluation of the Disease

Argininemia or arginase-1 deficiency constitutes a rare, genetic, metabolic disorder caused by mutations in arginase 1—the last enzyme of the urea cycle—that hydrolyses L-arginine to ornithine and urea. The disease is associated with progressive development of spasticity and other symptoms, including seizures, developmental delay, cognitive impairment, and hepatic pathology. The present review attempts to summarize the current knowledge on the pathophysiology of the disease and highlight novel methods for its evaluation. Different factors, such as the accumulation of arginine, ammonia, and guanidino compounds, act as neurotoxins and may account for the neurological sequelae observed in the disease. New markers, such as arginine/ornithine ratio along with metabolomics, machine learning algorithms, and genetic methods, can be useful in the early diagnosis of argininemia, while mobile phone apps can assist argininemic patients in adhering to the strict diet required. Neurophysiology, multi-modal imaging, and new modelling methods, such as induced pluripotent stem cells, hold promise for providing new insights into the pathophysiology of the disease. There are still many uncertainties regarding the underlying mechanisms of argininemia, but the use of novel modelling methods and new technology can lead to the decipherment of its pathophysiology, improvement of diagnostic accuracy, and better disease management

AQP4 Tag Single Nucleotide Polymorphisms in Patients with Traumatic Brain Injury

Accumulating evidence suggests that the extent of brain injury and the clinical outcome after traumatic brain injury (TBI) are modulated, to some degree, by genetic variants. Aquaporin-4 (AQP4) is the predominant water channel in the central nervous system and plays a critical role in controlling the water content of brain cells and the development of brain edema after TBI. We sought to investigate the influence of the AQP4 gene region on patient outcome after TBI by genotyping tag single nucleotide polymorphisms (SNPs) along AQP4 gene. A total of 363 patients with TBI (19.6% female) were prospectively evaluated. Data including the Glasgow Coma Scale (GCS) scores at admission, the presence of intracranial hemorrhage, and the 6-month Glasgow Outcome Scale (GOS) scores were collected. Seven tag SNPs across the AQP4 gene were identified based on the HapMap data. Using logistic regression analyses, SNPs and haplotypes were tested for associations with 6-month GOS after adjusting for age, GCS score, and sex. Significant associations with TBI outcome were detected for rs3763043 (OR [95% confidence interval (CI)]: 5.15 [1.60-16.5], p=0.006, for recessive model), rs3875089 (OR [95% CI]: 0.18 [0.07-0.50] p=0.0009, for allele difference model), and a common haplotype of AQP4 tag SNPs (OR [95% CI]: 2.94, [1.34-6.36], p=0.0065). AQP4 tag SNPs were not found to influence the initial severity of TBI or the presence of intracranial hemorrhages. In conclusion, the present study provides evidence for possible involvement of genetic variations in AQP4 gene in the functional outcome of patients with TBI