Acute Brain Insults Research Articles

Delayed levodopa-responsive parkinsonism following acute midbrain injury

Acute midbrain injury may cause both hyperkinetic movement disorders and parkinsonism. The temporal interval between the insult and the emergence of hyperkinetic disorders can last years. A delayed appearance of parkinsonism, on the other hand, was rarely described. We present three cases of male patients (50-, 58- and 28-year-old) who developed levodopa-responsive parkinsonism 20, 8 and two years, respectively, after acute brain insult involving the midbrain. Insults included subcortical intracerebral hemorrhage dissecting into the midbrain, embolic basilar occlusion and trauma. A fluorodopa scan, performed in two cases, revealed reduced striatal uptake. All individuals improved on low doses of levodopa and developed motor fluctuations shortly after levodopa was introduced. We conclude that delayed, levodopa-responsive parkinsonism following midbrain injury should be recognized in the relevant clinical setup. Possible mechanisms include age-related loss of dopaminergic neurons superimposed on acute injury and secondary neurodegeneration.

Utility of magnetic resonance imaging of brain in neurocritically ill children in pediatric intensive care unit: A single-center retrospective observational study

Abstract Background: Brain magnetic resonance imaging (MRI) was increasingly performed in children admitted in pediatric intensive care unit (PICU) with acute nontraumatic neurological disorders. The study aimed to describe neuroimaging findings and contribution of brain MRI in children admitted with acute encephalopathy admitted in PICU as well as adverse events during procedure. Subjects and Methods: Retrospective chart of all children with nontraumatic acute brain insults required MRI of brain admitted in PICU from January 2019 to December 2021. Demographic, clinical diagnosis, ICU therapies, and pertinent neurodiagnostic data were collected into a structured data collection sheet. The neurodiagnostic findings, contribution in the clinical management either as diagnostic, therapeutic, or prognostic as well as any adverse events during procedure and transport were also collected. All transport and procedure was done by pediatric intensive care team. Appropriate descriptive and analytical statistical tests were applied. Results: Eight two had brain MRI during the study period. The median age (year) was 3.0 (2 mo.-16 years) the most common admitting diagnoses were central nervous system infections in 39 (47.5%) and Status epilepticus in 7 (8%) cases. Neurodiagnostic categories of MRI were inflammatory in 34 (41.5%) and vascular/ischemia in 23 (28%) cases. Brain MRI was contributory in 57 (69.5%) cases in management of child as diagnostic in 41 (71.9%), prognostic in 15 (26%) therapeutic in 1 (1.7%) while noncontributory in 25 (30%) cases. No adverse events were reported during MRI. Conclusions: Brain MRI was helpful for the diagnosis as well as prognosis for acute neurocritically ill children in PICU and associated with very few minor adverse events.

CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage

Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury.

The impact of circulatory arrest with selective antegrade cerebral perfusion on brain functional connectivity and postoperative cognitive function

Aortic surgery is one of the most challenging types of surgeries, which is possibly related to cognitive sequelae. We aimed to investigate the changes in resting-state functional connectivity (rsFC) associated with intraoperative circulatory arrest (CA) in aortic surgery, exploring the relationship between the altered connectivity and postoperative cognitive functions. Thirty-eight patients participated in this study (14 with CA, 24 without). Functional magnetic resonance imaging was scanned on the fifth day after surgery or after the resolution of delirium if it was developed. We assessed the differences in the development of postoperative cognitive changes and rsFC between patients with and without CA. The occurrence of postoperative delirium and postoperative cognitive dysfunction was not significantly different between the patients with and without the application of CA. However, patients with CA showed increased in posterior cingulate cortex-based connectivity with the right superior temporal gyrus, right precuneus, and right hippocampus, and medial prefrontal cortex-based connectivity with the dorsolateral prefrontal cortex. The application of moderate hypothermic CA with unilateral antegrade cerebral perfusion is unlikely to affect aspects of postoperative cognitive changes, whereas it may lead to increased rsFC of the default mode network at a subclinical level following acute brain insults.

P7C3-A20 Attenuates Microglial Inflammation and Brain Injury after ICH through Activating the NAD+/Sirt3 Pathway.

Intracerebral hemorrhage (ICH) is lethal but lacks effective therapies. Nicotinamide adenine dinucleotide (NAD+) is a central metabolite indispensable for a broader range of fundamental intracellular biological functions. Reduction of NAD+ usually occurs after acute brain insults, and supplementation of NAD+ has been proven neuroprotective. P7C3-A20 is a novel compound featuring its ability to facilitate the flux of NAD+. In this study, we sought to determine the potential therapeutic value of P7C3-A20 in ICH. In collagenase-induced ICH mouse models, we found that P7C3-A20 treatment could diminish lesion volume, reduce blood-brain barrier (BBB) damage, mitigate brain edema, attenuate neural apoptosis, and improve neurological outcomes after ICH. Further, RNA sequencing and subsequent experiments revealed that ICH-induced neuroinflammation and microglial proinflammatory activities were significantly suppressed following P7C3-A20 treatment. Mitochondrial damage is an important trigger of inflammatory response. We examined mitochondrial morphology and function and found that P7C3-A20 could attenuate OxyHb-induced impairment of mitochondrial dynamics and functions in vitro. Mechanistically, Sirt3, an NAD+-dependent deacetylase located in mitochondria, was then found to play a vital role in the protection of P7C3-A20 against mitochondrial damage and inflammatory response. In rescue experiments, P7C3-A20 failed to exert those protective effects in microglia-specific Sirt3 conditional knockout (CKO) mice. Finally, preclinical research revealed a correlation between the plasma NAD+ level and the neurological outcome in ICH patients. These results demonstrate that P7C3-A20 is a promising therapeutic agent for neuroinflammatory injury after ICH and exerts protective actions, at least partly, in a Sirt3-dependent manner.

Should individual timeline and serial CT/MRI panels of all patients be presented in acute brain insult cohorts? A pilot study of 45 patients with decompressive craniectomy after aneurysmal subarachnoid hemorrhage

PurposeOur review of acute brain insult articles indicated that the patients’ individual (i) timeline panels with the defined time points since the emergency call and (ii) serial brain CT/MRI slice panels through the neurointensive care until death or final brain tissue outcome at 12 months or later are not presented.MethodsWe retrospectively constructed such panels for the 45 aneurysmal subarachnoid hemorrhage (aSAH) patients with a secondary decompressive craniectomy (DC) after the acute admission to neurointensive care at Kuopio University Hospital (KUH) from a defined population from 2005 to 2018. The patients were indicated by numbers (1.–45.) in the pseudonymized panels, tables, results, and discussion. The timelines contained up to ten defined time points on a logarithmic time axis until death (n=25; 56%) or 3 years (n=20; 44%). The brain CT/MRI panels contained a representative slice from the following time points: SAH diagnosis, after aneurysm closure, after DC, at about 12 months (20 survivors).ResultsThe timelines indicated re-bleeds and allowed to compare the times elapsed between any two time points, in terms of workflow swiftness. The serial CT/MRI slices illustrated the presence and course of intracerebral hemorrhage (ICH), perihematomal edema, intraventricular hemorrhage (IVH), hydrocephalus, delayed brain injury, and, in the 20 (44%) survivors, the brain tissue outcome.ConclusionsThe pseudonymized timeline panels and serial brain imaging panels, indicating the patients by numbers, allowed the presentation and comparison of individual clinical courses. An obvious application would be the quality control in acute or elective medicine for timely and equal access to clinical care.

Time and age dependent regulation of neuroinflammation in a rat model of mesial temporal lobe epilepsy: Correlation with human data.

Acute brain insults trigger diverse cellular and signaling responses and often precipitate epilepsy. The cellular, molecular and signaling events relevant to the emergence of the epileptic brain, however, remain poorly understood. These multiplex structural and functional alterations tend also to be opposing - some homeostatic and reparative while others disruptive; some associated with growth and proliferation while others, with cell death. To differentiate pathological from protective consequences, we compared seizure-induced changes in gene expression hours and days following kainic acid (KA)-induced status epilepticus (SE) in postnatal day (P) 30 and P15 rats by capitalizing on age-dependent differential physiologic responses to KA-SE; only mature rats, not immature rats, have been shown to develop spontaneous recurrent seizures after KA-SE. To correlate gene expression profiles in epileptic rats with epilepsy patients and demonstrate the clinical relevance of our findings, we performed gene analysis on four patient samples obtained from temporal lobectomy and compared to four control brains from NICHD Brain Bank. Pro-inflammatory gene expressions were at higher magnitudes and more sustained in P30. The inflammatory response was driven by the cytokines IL-1β, IL-6, and IL-18 in the acute period up to 72 h and by IL-18 in the subacute period through the 10-day time point. In addition, a panoply of other immune system genes was upregulated, including chemokines, glia markers and adhesion molecules. Genes associated with the mitogen activated protein kinase (MAPK) pathways comprised the largest functional group identified. Through the integration of multiple ontological databases, we analyzed genes belonging to 13 separate pathways linked to Classical MAPK ERK, as well as stress activated protein kinases (SAPKs) p38 and JNK. Interestingly, genes belonging to the Classical MAPK pathways were mostly transiently activated within the first 24 h, while genes in the SAPK pathways had divergent time courses of expression, showing sustained activation only in P30. Genes in P30 also had different regulatory functions than in P15: P30 animals showed marked increases in positive regulators of transcription, of signaling pathways as well as of MAPKKK cascades. Many of the same inflammation-related genes as in epileptic rats were significantly upregulated in human hippocampus, higher than in lateral temporal neocortex. They included glia-associated genes, cytokines, chemokines and adhesion molecules and MAPK pathway genes. Uniquely expressed in human hippocampus were adaptive immune system genes including immune receptors CDs and MHC II HLAs. In the brain, many immune molecules have additional roles in synaptic plasticity and the promotion of neurite outgrowth. We propose that persistent changes in inflammatory gene expression after SE leads not only to structural damage but also to aberrant synaptogenesis that may lead to epileptogenesis. Furthermore, the sustained pattern of inflammatory genes upregulated in the epileptic mature brain was distinct from that of the immature brain that show transient changes and are resistant to cell death and neuropathologic changes. Our data suggest that the epileptogenic process may be a result of failed cellular signaling mechanisms, where insults overwhelm the system beyond a homeostatic threshold.

Region-Specific Vulnerability of the Amygdala to Injury-Induced Spreading Depolarization.

Spreading depolarization (SD), a self-propagated wave of transient depolarization, regularly occurs in the cortex after acute brain insults and is now referred as an important diagnostic and therapeutic target in patients with acute brain injury. Here, we show that the amygdala, the limbic structure responsible for post-injury neuropsychological symptoms, exhibits strong regional heterogeneity in vulnerability to SD with high susceptibility of its basolateral (BLA) region and resilience of its centromedial (CMA) region to triggering SD by acute focal damage. The BLA micro-injury elicited SD twice as often compared with identical injury of the CMA region (71% vs. 33%). Spatiotemporal features of SDs triggered in the amygdala indicated diverse patterns of the SD propagation to the cortex. Our results suggest that even relatively small cerebral structures can exhibit regional gradients in their susceptibility to SD and the heterogeneity may contribute to the generation of complex SD patterns in the injured brain.

Microglia subtypes show substrate- and time-dependent phagocytosis preferences and phenotype plasticity.

Microglia are phagocytosis-competent CNS cells comprising a spectrum of subtypes with beneficial and/or detrimental functions in acute and chronic neurodegenerative disorders. The heterogeneity of microglia suggests differences in phagocytic activity and phenotype plasticity between microglia subtypes. To study these issues, primary murine glial cultures were cultivated in the presence of serum, different growth factors and cytokines to obtain M0-like, M1-like, and M2-like microglia as confirmed by morphology, M1/M2 gene marker expression, and nitric oxide assay. Single-cell analysis after 3 hours of phagocytosis of E.coli particles or IgG-opsonized beads showed equal internalization by M0-like microglia, whereas M1-like microglia preferably internalized E.coli particles and M2-like microglia preferably internalized IgG beads, suggesting subtype-specific preferences for different phagocytosis substrates. Time-lapse live-cells imaging over 16 hours revealed further differences between microglia subtypes in phagocytosis preference and internalization dynamics. M0- and, more efficiently, M1-like microglia continuously internalized E.coli particles for 16 hours, whereas M2-like microglia discontinued internalization after approximately 8 hours. IgG beads were continuously internalized by M0- and M1-like microglia but strikingly less by M2-like microglia. M2-like microglia initially showed continuous internalization similar to M0-like microglia but again discontinuation of internalization after 8 hours suggesting that the time of substrate exposure differently affect microglia subtypes. After prolonged exposure to E.coli particles or IgG beads for 5 days all microglia subtypes showed increased internalization of E.coli particles compared to IgG beads, increased nitric oxide release and up-regulation of M1 gene markers, irrespectively of the phagocytosis substrate, suggesting phenotype plasticity. In summary, microglia subtypes show substrate- and time-dependent phagocytosis preferences and phenotype plasticity. The results suggest that prolonged phagocytosis substrate exposure enhances M1-like profiles and M2-M1 repolarization of microglia. Similar processes may also take place in conditions of acute and chronic brain insults when microglia encounter different types of phagocytic substrates.

Electrographic Seizures in Neonates with a High Risk of Encephalopathy.

Background: Neonatal encephalopathy is caused by a wide variety of acute brain insults in newborns and presents with a spectrum of neurologic dysfunction, such as consciousness disturbance, seizures, and coma. The increased excitability in the neonatal brain appears to be highly susceptible to seizures after a variety of insults, and seizures may be the first clinical sign of a serious neurologic disorder. Subtle seizures are common in the neonatal period, and abnormal clinical paroxysmal events may raise the suspicion of neonatal seizures. Continuous video electroencephalographic (EEG) monitoring is the gold standard for the diagnosis of neonatal seizures. The aim of this study was to identify the prevalence of electrographic seizures and the impact of monitoring in neonates with a high risk of encephalopathy. Methods: We conducted this prospective cohort study in a tertiary neonatal intensive care unit over a 4-year period. Neonates with a high risk of encephalopathy who were receiving continuous video EEG monitoring were eligible. The patients were divided into 2 groups: (1) acute neonatal encephalopathy (ANE) and (2) other high-risk encephalopathy conditions (OHRs). The neonates’ demographic characteristics, etiologies, EEG background feature, presence of electrographic seizures and the impact of monitoring were analyzed. Results: A total of 71 neonates with a high risk of encephalopathy who received continuous video EEG monitoring were enrolled. In this consecutive cohort, 42 (59.2%) were monitored for ANE and 29 (40.8%) were monitored for OHRs. At the time of starting EEG monitoring, 54 (76.1%) of the neonates were term infants. The median gestational age at monitoring was 39 weeks (interquartile range, 37–41 weeks). The median total EEG monitoring duration was 64.7 h (interquartile range, 22.2–72.4 h). Electrographic seizures were captured in 25 of the 71 (35.2%) neonates, of whom 20 (80%) had electrographic-only seizures without clinical correlation. Furthermore, of these 20 neonates, 13 (65%) developed electrographic status epilepticus. Electrographic seizures were most commonly found in the ANE group (17, 40.5%) than in the OHRs group (8, 27.6%) (p = 0.013). Besides, normal/mild abnormality and inactive EEG background were less electrographic seizure than moderate and major abnormality EEG background (2 of 30, 6.7% vs. 23 of 41, 56.1%, p < 0.001). Finally, continuous video EEG monitoring excluded the diagnosis of electrographic seizures in two-thirds of the monitored neonates who had paroxysmal events mimicking seizures and led to a change in clinical management in 39.4% of the neonates. Conclusions: Our findings showed that monitoring could accurately detect seizures, and that it could be used to guide seizure medication management. Therefore, continuous video EEG monitoring has important clinical management implications in neonates with a high risk of encephalopathy.

Stem cell-derived extracellular vesicle therapy for acute brain insults and neurodegenerative diseases

Stem cell-based therapy is a promising approach for treating a variety of disorders, including acute brain insults and neurodegenerative diseases. Stem cells such as mesenchymal stem cells (MSCs) secrete extracellular vesicles (EVs), circular membrane fragments (30 nm−1 μm) that are shed from the cell surface, carrying several therapeutic molecules such as proteins and microRNAs. Because EV-based therapy is superior to cell therapy in terms of scalable production, biodistribution, and safety profiles, it can be used to treat brain diseases as an alternative to stem cell therapy. This review presents evidences evaluating the role of stem cell-derived EVs in stroke, traumatic brain injury, and degenerative brain diseases, such as Alzheimer’s disease and Parkinson’ disease. In addition, stem cell-derived EVs have better profiles in biocompatibility, immunogenicity, and safety than those of small chemical and macromolecules. The advantages and disadvantages of EVs compared with other strategies are discussed. Even though EVs obtained from native stem cells have potential in the treatment of brain diseases, the successful clinical application is limited by the short half-life, limited targeting, rapid clearance after application, and insufficient payload. We discuss the strategies to enhance the efficacy of EV therapeutics. Finally, EV therapies have yet to be approved by the regulatory authorities. Major issues are discussed together with relevant advances in the clinical application of EV therapeutics.

Risk factors that predict delayed seizure detection on continuous electroencephalogram (cEEG) in a large sample size of critically ill patients.

SummaryObjectiveMajority of seizures are detected within 24 hours on continuous EEG (cEEG). Some patients have delayed seizure detection after 24 hours. The purpose of this research was to identify risk factors that predict delayed seizure detection and to determine optimal cEEG duration for various patient subpopulations.MethodsWe retrospectively identified all patients ≥18 years of age who underwent cEEG at Cleveland clinic during calendar year 2016. Clinical and EEG data for all patients and time to seizure detection for seizure patients were collected.ResultsTwenty‐four hundred and two patients met inclusion criteria. Of these, 316 (13.2%) had subclinical seizures. Sixty‐five (20.6%) patients had delayed seizures detection after 24 hours. Seizure detection increased linearly till 36 hours of monitoring, and odds of seizure detection increased by 46% for every additional day of monitoring. Delayed seizure risk factors included stupor (13.2% after 48 hours, P = .031), lethargy (25.9%, P = .013), lateralized (LPDs) (27.7%, P = .029) or generalized periodic discharges (GPDs) (33.3%, P = .022), acute brain insults (25.5%, P = .036), brain bleeds (32.8%, P = .014), especially multiple concomitant bleeds (61.1%, P < .001), altered mental status (34.7%, P = .001) as primary cEEG indication, and use of antiseizure medications (27.8%, P < .001) at cEEG initiation.SignificanceGiven the linear seizure detection trend, 36 hours of standard monitoring appears more optimal than 24 hours especially for high‐risk patients. For awake patients without epileptiform discharges, <24 hours of monitoring appears sufficient. Previous studies have shown that coma and LPDs predict delayed seizure detection. We found that stupor and lethargy were also associated with delayed seizure detection. LPDs and GPDs were associated with delayed seizures. Other delayed seizure risk factors included acute brain insults, brain bleeds especially multiple concomitant bleeds, altered mental status as primary cEEG indication, and use of ASMs at cEEG initiation. Longer cEEG (≥48 hours) is suggested for these high‐risk patients.

Evaluation and Management of First-Time Seizure in Adults.

First seizures are often perceived as devastating events by patients and their families due to the fear of having a life-long disease. One in 10 people experiences one or more seizures during their lifetime, while 1 in 26 people develops epilepsy. Acute symptomatic seizures are often related to a provoking factor or an acute brain insult and typically do not recur. Careful history and clinical examination should guide clinicians' management plans. Electroencephalography and brain imaging, preferably with epilepsy-specific magnetic resonance imaging, may help characterize both etiology and risk of seizure recurrence. Antiepileptic drugs should be initiated in patients with newly diagnosed epilepsy. In patients without an epilepsy diagnosis, the decision to prescribe drugs depends on individual risk factors for seizure recurrence and possible complications from seizures, which should be discussed with the patient. Counseling about driving and lifestyle modifications should be provided early, often at the first seizure encounter.

Calcium Permeable-AMPA Receptors and Excitotoxicity in Neurological Disorders.

Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca2+ influx-triggered excitotoxicity through Ca2+-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.

Scopolamine prevents aberrant mossy fiber sprouting and facilitates remission of epilepsy after brain injury

Prevention or modification of acquired epilepsy in patients at risk is an urgent, yet unmet, clinical need. Following acute brain insults, there is an increased risk of mesial temporal lobe epilepsy (mTLE), which is often associated with debilitating comorbidities and reduced life expectancy. The latent period between brain injury and the onset of epilepsy may offer a therapeutic window for interfering with epileptogenesis. The pilocarpine model of mTLE is widely used in the search for novel antiepileptogenic treatments. Recent biochemical studies indicated that cholinergic mechanisms play a role in the epileptogenic alterations induced by status epilepticus (SE) in this and other models of mTLE, which prompted us to evaluate whether treatment with the muscarinic antagonist scopolamine during the latent period after SE is capable of preventing or modifying epilepsy and associated behavioral and cognitive alterations in female Sprague-Dawley rats. First, in silico pharmacokinetic modeling was used to select a dosing protocol by which M-receptor inhibitory brain levels of scopolamine are maintained during prolonged treatment. This protocol was verified by drug analysis in vivo. Rats were then treated twice daily with scopolamine over 17 days after SE, followed by drug wash-out and behavioral and video/EEG monitoring up to ~6 months after SE. Compared to vehicle controls, rats that were treated with scopolamine during the latent period exhibited a significantly lower incidence of spontaneous recurrent seizures during periods of intermittent recording in the chronic phase of epilepsy, less behavioral excitability, less cognitive impairment, and significantly reduced aberrant mossy fiber sprouting in the hippocampus. The present data may indicate that scopolamine exerts antiepileptogenic/disease-modifying activity in the lithium-pilocarpine rat model, possibly involving increased remission of epilepsy as a new mechanism of disease-modification. For evaluating the rigor of the present data, we envision a study that more thoroughly addresses the gender bias and video-EEG recording limitations of the present study.

Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction

Extracellular ATP is a danger signal to the brain and contributes to neurodegeneration in animal models of Alzheimer's disease through its extracellular catabolism by CD73 to generate adenosine, bolstering the activation of adenosine A2A receptors (A2AR). Convulsive activity leads to increased ATP release, with the resulting morphological alterations being eliminated by A2AR blockade. However, it is not known if upon convulsions there is a CD73-mediated coupling between ATP release and A2AR overactivation, causing neurodegeneration. We now show that kainate-induced convulsions trigger a parallel increase of ATP release and of CD73 and A2AR densities in synapses and astrocytes of the mouse hippocampus. Notably, the genetic deletion of CD73 attenuates neuronal degeneration but has no impact on astrocytic modifications in the hippocampus upon kainate-induced convulsions. Furthermore, kainate-induced convulsions cause a parallel deterioration of hippocampal long-term potentiation (LTP) and hippocampal-dependent memory performance, which is eliminated by knocking out CD73. This demonstrates the key role of the ATP release/CD73/A2AR pathway to selectively control synaptic dysfunction and neurodegeneration following an acute brain insult, paving the way to consider CD73 as a new therapeutic target to prevent neuronal damage upon acute brain damage.

White Matter Injury After Intracerebral Hemorrhage.

Spontaneous intracerebral hemorrhage (ICH) accounts for 15% of all stroke cases. ICH is a devastating form of stroke associated with high morbidity, mortality, and disability. Preclinical studies have explored the mechanisms of neuronal death and gray matter damage after ICH. However, few studies have examined the development of white matter injury (WMI) following ICH. Research on WMI indicates that its pathophysiological presentation involves axonal damage, demyelination, and mature oligodendrocyte loss. However, the detailed relationship and mechanism between WMI and ICH remain unclear. Studies of other acute brain insults have indicated that WMI is strongly correlated with cognitive deficits, neurological deficits, and depression. The degree of WMI determines the short- and long-term prognosis of patients with ICH. This review demonstrates the structure and functions of the white matter in the healthy brain and discusses the pathophysiological mechanism of WMI following ICH. Our review reveals that the development of WMI after ICH is complex; therefore, comprehensive treatment is essential. Understanding the relationship between WMI and other brain cells may reveal therapeutic targets for the treatment of ICH.

Roles of N-myc downstream-regulated gene 2 in the central nervous system: molecular basis and relevance to pathophysiology.

N-myc downstream-regulated gene 2 (NDRG2) is a member of the NDRG family, whose members have multiple functions in cell proliferation, differentiation, and stress responses. NDRG2 is widely distributed in the central nervous system and is uniquely expressed by astrocytes; however, its role in brain function remains elusive. The clinical relevance of NDRG2 and the molecular mechanisms in which it participates have been reported by studies using cultured cells and specimens of patients with neurological disorders. In recent years, genetic tools, including several lines of Ndrg2-knockout mice and virus-mediated gene transfer, have improved understanding of the roles of NDRG2 in vivo. This review aims to provide an update of recent growing in vivo evidence that NDRG2 is involved in brain function, focusing on research of Ndrg2-knockout mice with neurological disorders such as brain tumors, chronic neurodegenerative diseases, and acute brain insults including brain injury and cerebral stroke. These studies demonstrate that NDRG2 plays diverse roles in the regulation of astrocyte reactivity, blood-brain barrier integrity, and glutamate excitotoxicity. Further elucidation of the roles of NDRG2 and their molecular basis may provide novel therapeutic approaches for various neurological disorders.

CDK4 and CDK5 Inhibition Have Comparable Mild Hypothermia Effects in Preventing Drp1-Dependent Mitochondrial Fission and Neuron Death Induced by MPP.

Mild hypothermia has promising effects in the treatment of acute brain insults and also affects cell cycle progression. Mitochondrial dynamics, fusion and fission, are changed along with the cell cycle and disrupted in neurodegenerative diseases, including Parkinson's disease (PD). However, the effects of hypothermia on aberrant mitochondrial dynamics in PD remain unknown. We hypothesized that mild hypothermia protects neurons by regulating cell cycle-dependent protein expression and mitochondrial dynamics in a 1-methyl-4-phenylpyridinium (MPP+)-induced cell model of PD. We found that the hypothermia treatment at 32°C prevented MPP+-induced neuron death; however, 32°C treatment itself also reduced cell viability. This reduction was associated with cell cycle arrest and downregulation of cyclin-dependent kinase 4 (CDK4) in proliferating human SK-N-SH neuroblastoma cells but upregulation in well-differentiated primary rat cortical neurons. In both types of neurons, hypothermia upregulated p27 (an endogenous inhibitor of CDKs) and p35 (CDK5 activator) protein expression. Treatment with hypothermia, or a selective CDK4 inhibitor, or roscovitine (CDK5 inhibitor) prevented MPP+-induced mitochondrial fission, upregulation of mitochondrial fission protein dynamin-related protein 1 (Drp1), and neuron death. In addition, overexpression of dominant negative mutant Drp1K38A improved MPP+-induced mitochondrial fission while overexpression of wild-type Drp1 blunted the prevention of mitochondrial fission by hypothermia as well as CDK4 inhibitor and roscovitine. These results elucidate that hypothermia may inhibit CDK4 and CDK5 activation by upregulating p27 and p35 expression to prevent Drp1-dependent mitochondrial fission and neuron loss after MPP+ treatment. CDK4 and CDK5 inhibition imitates the neuroprotective functions of hypothermia as a potential therapy for PD.

Anti-Epileptogenic Effects of Antiepileptic Drugs.

Generally, the prevalence of epilepsy does not exceed 0.9% of the population and approximately 70% of epilepsy patients may be adequately controlled with antiepileptic drugs (AEDs). Moreover, status epilepticus (SE) or even a single seizure may produce neurodegeneration within the brain and SE has been recognized as one of acute brain insults leading to acquired epilepsy via the process of epileptogenesis. Two questions thus arise: (1) Are AEDs able to inhibit SE-induced neurodegeneration? and (2) if so, can a probable neuroprotective potential of particular AEDs stop epileptogenesis? An affirmative answer to the second question would practically point to the preventive potential of a given neuroprotective AED following acute brain insults. The available experimental data indicate that diazepam (at low and high doses), gabapentin, pregabalin, topiramate and valproate exhibited potent or moderate neuroprotective effects in diverse models of SE in rats. However, only diazepam (at high doses), gabapentin and pregabalin exerted some protective activity against acquired epilepsy (spontaneous seizures). As regards valproate, its effects on spontaneous seizures were equivocal. With isobolography, some supra-additive combinations of AEDs have been delineated against experimental seizures. One of such combinations, levetiracetam + topiramate proved highly synergistic in two models of seizures and this particular combination significantly inhibited epileptogenesis in rats following status SE. Importantly, no neuroprotection was evident. It may be strikingly concluded that there is no correlation between neuroprotection and antiepileptogenesis. Probably, preclinically verified combinations of AEDs may be considered for an anti-epileptogenic therapy.