Brain Cell Survival Research Articles

Beneficial effects of metformin treatment on memory impairment.

Memory issues are a prevalent symptom in different neurodegenerative diseases and can also manifest in certain psychiatric conditions. Despite limited medications approved for treating memory problems, research suggests a lack of sufficient options in the market. Studies indicate that a significant percentage of elderly individuals experience various forms of memory disorders. Metformin, commonly prescribed for type 2 diabetes, has shown neuroprotective properties through diverse mechanisms. This study explores the potential of metformin in addressing memory impairments. The current research gathered its data by conducting an extensive search across electronic databases including PubMed, Web of Science, Scopus, and Google Scholar. Previous research suggests that metformin enhances brain cell survival and memory function in both animal and clinical models by reducing oxidative stress, inflammation, and cell death while increasing beneficial neurotrophic factors. The findings of the research revealed that metformin is an effective medication for enhancing various types of memory problems in numerous studies. Given the rising incidence of memory disorders, it is plausible to utilize metformin, which is an affordable and accessible drug. It is often recommended as a treatment to boost memory.

Testosterone upregulates glial cell line-derived neurotrophic factor (GDNF) and promotes neuroinflammation to enhance glioma cell survival and proliferation

BackgroundTestosterone contributes to male organism development, such as bone density, muscle development, and fat repartition. Estrogen (derived from testosterone) also contributes to female reproductive system development. Here, we investigated the effect of testosterone on glioma cells and brain neuron inflammation essential for cancer development and progression.MethodsThe human astrocyte and glioma cell lines were treated with 6 ng/ml exogenous testosterone in vitro. We performed cell counting kit-8, transwell, and wound healing assays to determine the effect of testosterone on glioma cell proliferation, migration, and invasion. The glioma cells were injected into the xenograft and treated with 5 µl concentrated testosterone. Transcriptional suppression of glial cell line-derived neurotrophic factor (GDNF) was performed to evaluate brain neuron inflammation and survival. The tumor tissues were assessed by hematoxylin–eosin staining and immunohistochemistry.ResultsTestosterone upregulates GDNF to stimulate proliferation, migration, and invasion of glioma cells. Pathologically, the augmentation of GDNF and cyclophilin A contributed to neuroprotection when treated with testosterone. Our investigation showed that testosterone contributes to brain neuron and astrocyte inflammation through the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2), glial fibrillary acid protein (GFAP), and sirtuin 5 (SIRT5), resulting in pro-inflammatory macrophages recruitments into the neural microenvironment. Mechanically, testosterone treatment regulates GDNF translocation from the glioma cells and astrocyte nuclei to the cytoplasm.ConclusionTestosterone upregulates GDNF in glioma cells and astrocytes essential for microglial proliferation, migration, and invasion. Testosterone contributes to brain tumor growth via GDNF and inflammation.Graphical The contribution of testosterone, macrophages, and astrocytes, in old neuron rescue, survival, and proliferation. During brain neuron inflammation, the organism activates and stimulates the neuron rescue through the enrichment of the old neuron microenvironment with growth factors such as GDNF, BDNF, SOX1/2, and MAPK secreted by the surrounding neurons and glial cells to maintain the damaged neuron by inflammation alive even if the axon is dead. The immune response also contributes to brain cell survival through the secretion of proinflammatory cytokines, resulting in inflammation maintenance. The rescued old neuron interaction with infiltrated macrophages contributes to angiogenesis to supplement the old neuron with more nutrients leading to metabolism activation and surrounding cell uncontrollable cell growth.

Benzaldehyde Attenuates the Fifth Stage Larval Excretory-Secretory Product of Angiostrongylus cantonensis-Induced Injury in Mouse Astrocytes via Regulation of Endoplasmic Reticulum Stress and Oxidative Stress.

Excretory–secretory products (ESPs) are the main research targets for investigating the hosts and helminths interaction. Parasitic worms can migrate to parasitic sites and avoid the host immune response by secreting this product. Angiostrongylus cantonensis is an important food-borne zoonotic parasite that causes severe neuropathological damage and symptoms, including eosinophilic meningitis or meningoencephalitis in humans. Benzaldehydes are organic compounds composed of a benzene ring and formyl substituents. This compound has anti-inflammatory and antioxidation properties. Previous studies showed that 3-hydroxybenzaldehyde (3-HBA) and 4-hydroxybenzaldehyde (4-HBA) can reduce apoptosis in A. cantonensis ESP-treated astrocytes. These results on the protective effect underlying benzaldehyde have primarily focused on cell survival. The study was designed to investigate the molecular mechanisms of endoplasmic reticulum stress (ER stress) and oxidative stress in astrocytes in A. cantonensis ESP-treated astrocytes and to evaluate the therapeutic consequent of 3-HBA and 4-HBA. First, we initially established the RNA-seq dataset in each group, including normal, ESPs, ESPs + 3-HBA, and ESPs + 4-HBA. We also found that benzaldehyde (3-HBA and 4-HBA) can stimulate astrocytes to express ER stress-related molecules after ESP treatment. The level of oxidative stress could also be decreased in astrocytes by elevating antioxidant activity and reducing ROS generation. These results suggested that benzaldehyde may be a potential therapeutic compound for human angiostrongyliasis to support brain cell survival by inducing the expression levels of ER stress- and oxidative stress-related pathways.

Anti-Inflammatory Therapies for Treatment of Inflammation-Related Preterm Brain Injury.

Despite the prevalence of preterm brain injury, there are no established neuroprotective strategies to prevent or alleviate mild-to-moderate inflammation-related brain injury. Perinatal infection and inflammation have been shown to trigger acute neuroinflammation, including proinflammatory cytokine release and gliosis, which are associated with acute and chronic disturbances in brain cell survival and maturation. These findings suggest the hypothesis that the inhibition of peripheral immune responses following infection or nonspecific inflammation may be a therapeutic strategy to reduce the associated brain injury and neurobehavioral deficits. This review provides an overview of the neonatal immunity, neuroinflammation, and mechanisms of inflammation-related brain injury in preterm infants and explores the safety and efficacy of anti-inflammatory agents as potentially neurotherapeutics.

Royal Jelly as an Intelligent Anti-Aging Agent-A Focus on Cognitive Aging and Alzheimer's Disease: A Review.

The astronomical increase of the world’s aged population is associated with the increased prevalence of neurodegenerative diseases, heightened disability, and extremely high costs of care. Alzheimer’s Disease (AD) is a widespread, age-related, multifactorial neurodegenerative disease that has enormous social and financial drawbacks worldwide. The unsatisfactory outcomes of available AD pharmacotherapy necessitate the search for alternative natural resources that can target the various underlying mechanisms of AD pathology and reduce disease occurrence and/or progression. Royal jelly (RJ) is the main food of bee queens; it contributes to their fertility, long lifespan, and memory performance. It represents a potent nutraceutical with various pharmacological properties, and has been used in a number of preclinical studies to target AD and age-related cognitive deterioration. To understand the mechanisms through which RJ affects cognitive performance both in natural aging and AD, we reviewed the literature, elaborating on the metabolic, molecular, and cellular mechanisms that mediate its anti-AD effects. Preclinical findings revealed that RJ acts as a multidomain cognitive enhancer that can restore cognitive performance in aged and AD models. It promotes brain cell survival and function by targeting multiple adversities in the neuronal microenvironment such as inflammation, oxidative stress, mitochondrial alterations, impaired proteostasis, amyloid-β toxicity, Ca excitotoxicity, and bioenergetic challenges. Human trials using RJ in AD are limited in quantity and quality. Here, the limitations of RJ-based treatment strategies are discussed, and directions for future studies examining the effect of RJ in cognitively impaired subjects are noted.

Megalencephaly Capillary Malformation Syndrome

AbstractMegalencephaly capillary malformation polymicrogyria (MCAP) syndrome is characterized by the sporadic occurrence of congenital and progressive megalencephaly, brain malformations including polymicrogyria, pre- and postnatal overgrowth with body asymmetry, cutaneous vascular malformations (including capillary malformation and cutis marmorata), digital anomalies connective tissue dysplasia (including skin and joint laxity), and developmental delay. In the past 10 years, the specific cause of the disease has been found in gain-of-function mutations of PIK3CA gene, mostly somatic/postzygotic but in rare cases also de novo germline. Such gene encodes for PI3K, a critical member of the PI3K-AKT-mTOR pathway: genetic changes lead to an over-activation of this signaling system, with increased vascular, limb, and brain cell development, progression, and survival. Interestingly, mutations in the same gene can cause other clinically heterogeneous syndromes, including CLOVE syndrome, macrodactyly, focal adipose overgrowth, epidermal nevi, facial infiltrating lipomatosis: all these syndromes (even if heterogeneous) are now considered a unique spectrum, known as PIK3CA-related overgrowth syndrome. On the contrary, a disease strictly similar to MCAP, characterized by megalencephaly, polymicrogyria, polydactyly, and hydrocephalus has been found to be caused by mutations in two other PI3K-AKT-mTOR-releted genes, AKT3 and PIK3R2, and for this reason is not included in the upper mentioned group of syndromes. With the exception of neurosurgery strategies for hydrocephalus and posterior fossa overcrowding, therapeutic options are nowadays limited, even if gene-targeted treatment protocols have been proposed and protocols with such agents (i.e., Arq092) are currently ongoing in small groups of patients with promising results.

Dysregulation of PI3K-Akt-mTOR pathway in brain of streptozotocin-induced type 2 diabetes mellitus in Wistar rats

BackgroundProteins of the insulin signaling pathway are needed for cell proliferation and development and glucose homeostasis. It is not known whether insulin signalling markers (Foxo1, Gsk3β) can be correlated with the expression on PI3K-Akt-mTOR pathway, which are needed for cell survival and maintenance of glucose homeostasis. In the present study, we studied the expression of Foxo1, Gsk3β and PI3K-Akt-mTOR in the brain of streptozotocin-induced type 2 diabetes mellitus Wistar rats.MethodsThe study was performed both in vitro (RIN5F cells) and in vivo (male Wistar rats). Gene expression of Nf-kB, IkB, Bax, Bcl-2 and Pdx1 gene was studied invitro by qRT-PCR in RIN5F cells. In STZ (65 mg/kg i.p.)-induced type 2 DM Wistar rats, blood glucose and insulin levels, iNOS, Foxo1, NF-κB, pGsk3β and PPAR-γ1 levels along with PI3k-Akt-mTOR were measured in brain tissue.ResultsRIN5F cells treated with STZ showed increase in the expression of NF-kB and Bax and decrease in IkB, Bcl-2 and PDX1. Brain tissue of STZ-induced type 2 DM animals showed a significant reduction in secondary messengers of insulin signalling (Foxo1) (P < 0.001) and Gsk3β (P < 0.01) and a significant alteration in the expression of phosphorylated-Akt (P < 0.001) mTOR (P < 0.01) and PI3K.ConclusionThese results suggest that STZ induces pancreatic β cell apoptosis by enhancing inflammation. Significant alterations in the expression brain insulin signaling and cell survival pathways seen in brain of STZ-treated animals implies that alterations neuronal apoptosis may have a role in altered glucose homeostasis seen in type 2 DM that may also explain the increased incidence of cognitive dysfunction seen in them.

Fluid balance concepts in medicine: Principles and practice.

The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water (TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment (mainly sodium salts) and in the intracellular compartment (mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume (EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.

Homeostasis and the concept of 'interstitial fluids hierarchy': Relevance of cerebrospinal fluid sodium concentrations and brain temperature control(Review).

In this review, the aspects and further developments of the concept of homeostasis are discussed also in the perspective of their possible impact in the clinical practice, particularly as far as psychic homeostasis is concerned. A brief historical survey and comments on the concept of homeostasis and allostasis are presented to introduce our proposal that is based on the classical assumption of the interstitial fluid (ISF) as the internal medium for multicellular organisms. However, the new concept of a hierarchic role of ISF of the various organs is introduced. Additionally, it is suggested that particularly for some chemico-physical parameters, oscillatory rhythms within their proper set-ranges should be considered a fundamental component of homeostasis. Against this background, we propose that the brain ISF has the highest hierarchic role in human beings, providing the optimal environment, not simply for brain cell survival, but also for brain complex functions and the oscillatory rhythms of some parameters, such as cerebrospinal fluid sodium and brain ISF pressure waves, which may play a crucial role in brain physio-pathological states. Thus, according to this proposal, the brain ISF represents the real internal medium since the maintenance of its dynamic intra-set-range homeostasis is the main factor for a free and independent life of higher vertebrates. Furthermore, the evolutionary links between brain and kidney and their synergistic role in H2O/Na balance and brain temperature control are discussed. Finally, it is surmised that these two interrelated parameters have deep effects on the Central Nervous System (CNS) higher integrative actions such those linked to psychic homeostasis.

Dietary DHA and health: cognitive function ageing.

DHA is a key nutritional n-3 PUFA and needs to be supplied by the human diet. DHA is found in significant amounts in the retinal and neuronal cell membranes due to its high fluidity. Indeed, DHA is selectively concentrated in the synaptic and retinal membranes. DHA is deemed to display anti-inflammatory properties and to reduce the risk of CVD. Consumption of larger amounts of DHA appears to reduce the risk of depression, bipolar disorder, schizophrenia and mood disorders. Conversely, it has been shown that loss of DHA from the nerve cell membrane leads to dysfunction of the central nervous system in the form of anxiety, irritability, susceptibility to stress, dyslexia, impaired memory and cognitive functions, and extended reaction times. DHA plays an important role in ensuring a healthy ageing, by thwarting macular degeneration, Alzheimer's disease, and other brain disorders at the same time as enhancing memory and strengthening neuroprotection in general. A reduced level of DHA is associated with cognitive decline during ageing. Different mechanisms for this fundamental DHA role have been put forward. Namely, neuroprotectin D1, a DHA derivative, may support brain cell survival and repair through neurotrophic, anti-apoptotic, and anti-inflammatory signalling. Many of the effects of DHA on the neurological system may be related to signalling connections, thus leading to the study of the related signalolipidomics. Therefore, the present review will focus on the influence of DHA deficiency upon ageing, with specific emphasis upon neurological disorders related to cognitive function and mental health.

Anti-ApoA-1 IgG serum levels predict worse poststroke outcomes.

Autoantibodies to apolipoprotein A-1 (anti-ApoA-1 IgG) were shown to predict major adverse cardiovascular events and promote atherogenesis. However, their potential relationship with clinical disability and ischaemic lesion volume after acute ischaemic stroke (AIS) remains unexplored. We included n = 76 patients admitted for AIS and we investigated whether baseline serum anti-ApoA-1 IgG levels could predict (i) AIS-induced clinical disability [assessed by the modified Rankin Scale (mRS)], and (ii) AIS-related ischaemic lesion volume [assessed by Computed Tomography (CT)]. We also evaluated the possible pro-apoptotic and pro-necrotic effects of anti-ApoA-1 IgG on human astrocytoma cell line (U251) using flow cytometry. High levels of anti-ApoA-1 IgG were retrieved in 15·8% (12/76) of patients. Increased baseline levels of anti-ApoA-1 IgG were independently correlated with worse mRS [β = 0·364; P = 0·002; adjusted odds ratio (OR): 1·05 (95% CI 1·01-1·09); P = 0·017] and CT-assessed ischaemic lesion volume [β = 0·333; P < 0·001; adjusted OR: 1·06 (95% CI 1·01-1·12); P = 0·048] at 3 months. No difference in baseline clinical, biochemical and radiological characteristics was observed between patients with high vs. low levels of anti-ApoA-1 IgG. Incubating human astrocytoma cells with anti-ApoA-1 IgG dose dependently induced necrosis and apoptosis of U251 cells in vitro. Anti-ApoA-1 IgG serum levels at AIS onset are associated with poorer clinical recovery and worse brain lesion volume 3 months after AIS. These observations could be partly explained by the deleterious effect of anti-ApoA-1 IgG on human brain cell survival in vitro and may have clinical implication in the prediction of poor outcome in AIS.

Breaking the Blood-Brain Barrier With Mannitol to Aid Stem Cell Therapeutics in the Chronic Stroke Brain.

Blood-brain barrier (BBB) permeabilizers, such as mannitol, can facilitate peripherally delivered stem cells to exert therapeutic benefits on the stroke brain. Although this BBB permeation-aided stem cell therapy has been demonstrated in the acute stage of stroke, such BBB permeation in the chronic stage of the disease remains to be examined. Adult Sprague-Dawley rats initially received sham surgery or experimental stroke via the 1-h middle cerebral artery occlusion (MCAo) model. At 1 month after the MCAo surgery, stroke animals were randomly assigned to receive human umbilical cord stem cells only (2 million viable cells), mannitol only (1.1 mol/L mannitol at 4°C), combined human umbilical cord stem cells (200,000 viable cells) and mannitol (1.1 mol/L mannitol at 4°C), and vehicle (phosphate-buffered saline) only. Stroke animals that received human umbilical cord blood cells alone or combined human umbilical cord stem cells and mannitol exhibited significantly improved motor performance and significantly better brain cell survival in the peri-infarct area compared to stroke animals that received vehicle or mannitol alone, with mannitol treatment reducing the stem cell dose necessary to afford functional outcomes. Enhanced neurogenesis in the subventricular zone accompanied the combined treatment of human umbilical cord stem cells and mannitol. We showed that BBB permeation facilitates the therapeutic effects of a low dose of peripherally transplanted stem cells to effectively cause functional improvement and increase neurogenesis in chronic stroke.

Non-additive effects of delayed connexin hemichannel blockade and hypothermia after cerebral ischemia in near-term fetal sheep.

Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia (n=8), hypothermia for 3 days (n=8), connexin hemichannel blockade (50 μmol/L intracerebroventricular over 1 hour followed by 50 μmol/L over 24 hours, n=8) or hypothermia plus hemichannel blockade (n=7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology (P<0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep.

Effects of Toxocara larvae on brain cell survival by in vitro model assessment

Neuroinvasive larvae of the common dog and cat roundworms, Toxocara canis and Toxocara cati, may cause severe neurological and neuropsychological disturbances in humans. Despite their pathogenic potential and high prevalence worldwide, little is known about their cell-specific influences and cerebral host-pathogen interactions in neurotoxocarosis. To address this discrepancy, a co-culture system of viable larvae with murine neuronal (CAD), oligodendrocytal (BO-1) and microglial (BV-2) cell lines has been established. Additionally, murine adult brain slices have been co-cultured with Toxocara larvae to consider complex organotypic cell-cell interplay. Cytotoxicity of larval presence was measured enzymatically and microscopically. Microscopic evaluation using trypan blue exclusion assay revealed to be less reliable and sensitive than the lactate dehydrogenase activity assay. Ultimately, even low numbers of both T. canis and T. cati larvae have impaired survival of differentiated CAD cells, which morphologically resemble primary neurons. In contrast, viability of oligodendrocytal and microglial cells as well as brain slices was not impaired by larval presence. Therefore, immune-mediated mechanisms or trauma by migrating larvae presumably induce the in vivo pathology rather than acute cytotoxic effects. Conclusively, the helminthic larvae co-culture system presented here is a valuable in vitro tool to study cell-specific effects of parasitic larvae and their products.

Melatonin Redox Activity. Its Potential Clinical Applications in Neurodegenerative Disorders

Neurodegeneration is the hallmark of many chronic progressive neurogical disorders characterized by specific clinical, morphological and biochemical features. Central nervous system is very sensitive to oxidative stress, which is considered as a key factor of neurodegenerative disorders. Therefore, many therapeutical strategies are focused on molecules with redox activity to re-establish the equilibrium between pro and antioxidants. Due to the fact that melatonin readily crosses the blood- brain-barrier, concomitant with its safety profile at the highest dosages makes this dietary supplement very useful in possible clinical application in neurodegeneration. Melatonin is currently marketed in several countries as a dietary supplement with no prescription. Clinical trials have shown different effectiveness of melatonin supplementation in several disorders, including neurodegenerative disorders. Melatonin has unique biochemical properties such as scavenging of hydroxyl, carbonate, alkoxyl, peroxyl and aryl cation radicals and stimulation of activities main antioxidative enzymes (glutathione peroxidase, superoxide dismutase etc.). Moreover, it can suppress nitric oxide synthase. The present paper highlighted the potential clinical role of melatonin in main neurodegenerative diseases including Alzheimer disease, Parkinson disease, amylotrophic lateral sclerosis and multiple sclerosis. Moreover, in this review the main molecular aspects of melatonin in brain cell protection and survival mechanisms were discussed. Therefore, melatonin is regarded as a potential therapeutical agent in clinical application in neurodegenerative disorders, but this findings needs to be confirmed by the larger, more well-designed clinical trials.

Rising stars: modulation of brain functions by astroglial type-1 cannabinoid receptors.

The type-1-cannabinoid (CB1 ) receptor is amongst the most widely expressed G protein-coupled receptors in the brain. In few decades, CB1 receptors have been shown to regulate a large array of functions from brain cell development and survival to complex cognitive processes. Understanding the cellular mechanisms underlying these functions of CB1 is complex due to the heterogeneity of the brain cell types on which the receptor is expressed. Although the large majority of CB1 receptors act on neurons, early studies pointed to a direct control of CB1 receptors over astroglial functions including brain energy supply and neuroprotection. In line with the growing concept of the tripartite synapse highlighting astrocytes as direct players in synaptic plasticity, astroglial CB1 receptor signaling recently emerged as the mediator of several forms of synaptic plasticity associated to important cognitive functions. Here, we shortly review the current knowledge on CB1 receptor-mediated astroglial functions. This functional spectrum is large and most of the mechanisms by which CB1 receptors control astrocytes, as well as their consequences in vivo, are still unknown, requiring innovative approaches to improve this new cannabinoid research field.

B26 Targeting Sphingosine-1-phosphate Metabolism/axis May Be Beneficial In Huntington Disease Models

Background Sphingosine-1-phosphate (S1P) is a potent signalling sphingolipid that acts as a high affinity agonist at five known G protein-coupled receptors, S1PR1-S1PR5, and regulates brain cell homeostasis and survival. S1P metabolism is quite complex and involves the action of different enzymes. S1P is synthesised by sphingosine kinase-1 and -2 (SPHK1 and 2) and degraded either by S1P-phosphate (SPP) or by S1P-lyase (SGPL1). Recent evidence indicates that pharmacological modulation of S1P metabolism/axis may represent a promising therapeutic approach for multiple disorders including neurodegenerative diseases. Aims Here, we aim to explore whether S1P metabolism/signalling pathway may have the potential to be molecularly targeted for developing new therapeutic strategies for the treatment of HD. Methods In vitro experiments were performed in mouse striatal-derived cells expressing wild-type (SThdh7/7) or mutant huntingtin (SThdh111/111). In vivo experiments were carried out in symptomatic R6/2 and YAC128 HD mouse models. Results Our findings reveal an overall aberrant expression of S1P metabolising enzymes both in HD cells and mouse brain tissues with increased levels of SGPL1, which might likely correlate with its increased activity and subsequent alteration of S1P bio-availability. Also, we found that targeting specific molecules in S1P/metabolism/axis activates pro-survival pathways in SThdh111/111 cells. Conclusion These results support the hypothesis of an aberrant metabolism of S1P in HD and indicate that the modulation of its signalling pathway may be beneficial. Thus, we believe S1P axis has the potential of providing the possibility to develop new therapeutic interventions for treating HD. This research is supported by Marie Curie International Incoming Fellowship (PIIF-GA-2011–300197) granted to V. M. within the 7th European Community Framework Programme.

Critical roles of mitochondria in brain activities of torpid Myotis ricketti bats revealed by a proteomic approach

Bats are the only mammals that fly and hibernate. Little is known about their overall metabolism in the brain during hibernation. In this study, brain proteins of torpid and active Myotis ricketti bats were fractionated and compared using a proteomic approach. Results showed that 21% (23 proteins) of identified proteins with significant expression changes were associated with amino acid metabolism and proteostasis. The expression levels of proteins involved in energy metabolism (15 proteins), cytoskeletal structure (18 proteins), and stress response (13 proteins) were also significantly altered in torpid bats. Over 30% (34 proteins) of differentially expressed proteins were associated with mitochondrial functions. Various post-translational modifications (PTMs) on PDHB, DLD, and ARG1 were detected, suggesting that bats use PTMs to regulate protein functions during torpor. Antioxidation and stress responses in torpid bats were similar to those of hibernated squirrels, suggesting a common strategy adopted by small hibernators against brain dysfunction. Since many amino acids that metabolize in mitochondria modulate neuronal transmissions, results of this study reveal pivotal roles of mitochondria in neural communication, metabolic regulation, and brain cell survival during bat hibernation. This article is part of a Special Issue entitled: Proteomics of non-model organisms. This study reveals the mechanisms used by bats to regulate brain activities during torpor. These mechanisms include post-translational modifications and differential expression of proteins involved in mitochondrial electron transport, anaerobic glycolysis, TCA cycle efflux, cytoskeletal plasticity, amino acid metabolism, vesicle structure, antioxidation defense, stress response, and proteostasis. Our study provides insights in metabolic regulation of flying mammals during torpor and common strategies used by small hibernators in response to hibernation. This article is part of a Special Issue entitled: Proteomics of non-model organisms.

Effects of olive polyphenols administration on nerve growth factor and brain-derived neurotrophic factor in the mouse brain

ObjectivePolyphenols are chemicals derived from plants known to possess antioxidant and anti-inflammatory properties. High intake of fruit and vegetables is believed to be beneficial to human health. Various studies have suggested that dietary polyphenols may protect against cancer and cardiometabolic and neurodegenerative diseases. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are neurotrophins that play key roles in brain cell development, growth, and survival. The aim of this study was to investigate whether or not administration of olive (Olea europaea L.) polyphenols could have an effect on NGF and BDNF content and the expression of their receptors, TrkA and TrkB, respectively, in the mouse brain. MethodsNGF and BDNF were measured by enzyme-linked immunosorbent assay. TrkA and TrkB were measured by Western blotting. ResultsWe found NGF and BDNF elevation in the hippocampus and olfactory bulbs and a decrease in the frontal cortex and striatum. These data were associated with potentiated expression of TrkA and TrkB in the hippocampus and olfactory bulbs but no differences between groups in the striatum and frontal cortex. Polyphenols did not affect some behavioral mouse parameters associated with stressing situations. ConclusionsAltogether, this study shows that olive polyphenols in the mouse may increase the levels of NGF and BDNF in crucial areas of the limbic system and olfactory bulbs, which play a key role in learning and memory processes and in the proliferation and migration of endogenous progenitor cells present in the rodent brain.

The good and bad of microglia/macrophages: new hope in stroke therapeutics

Ischemic stroke contributes up to 80% of total stroke incidence and is one of the leading causes of death and disability worldwide1,2. Noteworthily, the inflammatory responses triggered after ischemic stroke often amplify and exacerbate the ischemic lesion2. Insufficient blood supply to brain cells initiates the pathophysiology of ischemic stroke and results in a densely ischemic core surrounded by a poorly perfused region termed ischemic penumbra. Cells within the ischemic area become deprived of oxygen, glucose, and other nutrients. Since oxygen and glucose are critical fuels for brain cell survival, lack of these factors leads to dysfunction of neurons, glial cells, endothelial cells, and pericytes. Neuronal microenvironments are no longer tightly maintained and disruption of the blood brain barrier (BBB) occurs. Blood borne immune cells start to infiltrate through the disrupted vessel walls into the ischemic area and release inflammatory mediators, which exaggerate brain edema and promote cell death in the penumbra to result in secondary infarct lesion1,3. Accordingly, ischemic stoke patients who arrived to the hospital within a short time window (3–4.5 h1,2,4) after stroke incidence are commonly treated with the thrombolytic agent, recombinant tissue plasminogen activator (tPA, commonly called “clot buster”), in an attempt to restore perfusion and minimize brain damage1,2. For patients who have missed the short time frame, there is no safe and efficacious treatment that is currently available3. This is because the thrombus in the occluded artery has become too firm for tPA to dissolve. Moreover, the BBB disruption is likely to occur at this point, which would allow tPA to gain excess into the extravascular compartment. tPA residing in the extravascular compartment is associated with higher risk of intracranial hemorrhage and neurotoxicity5. Therefore, the beneficial effect of tPA is greatly compromised in patients with prolonged and untreated ischemic stroke. To develop effective treatments for these patients, it is essential to understand the complex and incompletely defined post ischemic inflammatory response mechanisms. This article highlights a recent work reported by Hu and colleagues6, which sheds new light into the future management of post-ischemic stroke inflammation.