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15 December 2018, Volume 13 Issue 12 Previous Issue    Next Issue

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Neuroprotective and neuroregenerative potential of pharmacologically-induced hypothermia with D-alanine D-leucine enkephalin in brain injury M. Grant Liska, Marci G. Crowley, Julian P. Tuazon, Cesar V. Borlongan 2018, 13 (12):  2029-2037.  doi: 10.4103/1673-5374.241427 Abstract ( 177 )   PDF (219KB) ( 273 )   Save Neurovascular disorders, such as traumatic brain injury and stroke, persist as leading causes of death and disability – thus, the search for novel therapeutic approaches for these disorders continues. Many hurdles have hindered the translation of effective therapies for traumatic brain injury and stroke primarily because of the inherent complexity of neuropathologies and an inability of current treatment approaches to adapt to the unique cell death pathways that accompany the disorder symptoms. Indeed, developing potent treatments for brain injury that incorporate dynamic and multiple disorder-engaging therapeutic targets are likely to produce more effective outcomes than traditional drugs. The therapeutic use of hypothermia presents a promising option which may fit these criteria. While regulated temperature reduction has displayed great promise in preclinical studies of brain injury, clinical trials have been far less consistent and associated with adverse effects, especially when hypothermia is pursued via systemic cooling. Accordingly, devising better methods of inducing hypothermia may facilitate the entry of this treatment modality into the clinic. The use of the delta opioid peptide D-alanine D-leucine enkephalin (DADLE) to pharmacologically induce temperature reduction may offer a potent alternative, as DADLE displays both the ability to cause temperature reduction and to confer a broad profile of other neuroprotective and neuroregenerative processes. This review explores the prospect of DADLE-mediated hypothermia to treat neurovascular brain injuries, emphasizing the translational steps necessary for its clinical translation. References | Related Articles | Metrics

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Roles and functions of Atp6ap2 in the brain Alexander Bracke, Oliver von Bohlen und Halbach 2018, 13 (12):  2038-2043.  doi: 10.4103/1673-5374.241428 Abstract ( 139 )   PDF (370KB) ( 268 )   Save   The classical renin-angiotensin system (RAS) in the body has been studied intensively in the last decades, since it is known that this system is involved in the regulation of blood pressure. Since nearly all members of the classical RAS have also been identified within the brain in the last decades and due to the existence of the blood-brain barrier, a RAS within the brain (bRAS) that is largely independent from the peripheral RAS has been postulated. All members of the angiotensin family as e.g., angiotensin II, angiotensin IV and angiotensin II (1–7) along with the respective receptors (e.g., angiotensin II receptor type 1 (AT1), angiotensin II receptor type 2 (AT2), angiotensin IV receptor (AT4), angiotensin II (1–7) receptor (Mas)) have been identified within the brain. Moreover, a receptor capable of binding renin and the renin precursor prorenin with high affinity has also been detected within the brain. This protein functions as a membrane receptor for (pro)renin and also represents a V-ATPase subunit and is therefore termed (P)RR or Atp6ap2, respectively. In this review we shed light on the (known as well as putative) roles and functions of Atp6ap2 in the brain under physiological and pathophysiological conditions. Related Articles | Metrics

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Magnesium sulfate and fetal neuroprotection: overview of clinical evidence Clément Chollat, Stéphane Marret 2018, 13 (12):  2044-2049.  doi: 10.4103/1673-5374.241441 Abstract ( 141 )   PDF (185KB) ( 246 )   Save Antenatal administration of magnesium sulfate is an important part of the neuroprotective strategy for preterm infants. Strong evidence from five randomized controlled trials and five meta-analyses has demonstrated that magnesium sulfate, when administered before preterm delivery, significantly reduces the risk of cerebral palsy at two years. Through secondary analyses of randomized controlled trials and other original clinical studies, this state-of-the-art review highlights the absence of serious adverse effects in both pregnant women and neonates, as well as the impact of maternal body mass index and preeclamptic status on the maternal and neonatal magnesium levels, which could influence the magnitude of the neuroprotective effect. Although antenatal magnesium sulfate is a cost-effective strategy, some practice surveys have demonstrated that the use of magnesium sulfate is not sufficient and that its use is heterogeneous, differing among different maternity wards. Since 2010, an increasing number of obstetrical societies have recommended its use to improve the neurological outcomes of preterm infants, especially the International Federation of Gynecology and Obstetrics and World Health Organization in 2015, and France in 2017. Considering the neuroprotective impact of magnesium sulfate when administered before delivery, postnatal administration should be considered, and its effects should be assessed using randomized controlled trials. Related Articles | Metrics

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Animal models of amyotrophic lateral sclerosis: a comparison of model validity Jessica R. Morrice, Cheryl Y. Gregory-Evans, Christopher A. Shaw 2018, 13 (12):  2050-2054.  doi: 10.4103/1673-5374.241445 Abstract ( 152 )   PDF (163KB) ( 327 )   Save Animal models are necessary to investigate the pathogenic features underlying motor neuron degeneration and for therapeutic development in amyotrophic lateral sclerosis (ALS). Measures of model validity allow for a critical interpretation of results from each model and caution from over-interpretation of experimental models. Face and construct validity refer to the similarity in phenotype and the proposed causal factor to the human disease, respectively. More recently developed models are restricted by limited phenotype characterization, yet new models hold promise for novel disease insights, thus highlighting their importance. In this article, we evaluate the features of face and construct validity of our new zebrafish model of environmentally-induced motor neuron degeneration and discuss this in the context of current environmental and genetic ALS models, including C9orf72, mutant Cu/Zn superoxide dismutase 1 and TAR DNA-binding protein 43 mouse and zebrafish models. In this mini-review, we discuss the pros and cons to validity criteria in each model. Our zebrafish model of environmentally-induced motor neuron degeneration displays convincing features of face validity with many hallmarks of ALS-like features, and weakness in construct validity. However, the value of this model may lie in its potential to be more representative of the pathogenic features underlying sALS cases, where environmental factors may be more likely to be involved in disease etiology than single dominant gene mutations. It may be necessary to compare findings between different strains and species modeling specific genes or environmental factors to confirm findings from ALS animal models and tease out arbitrary strain- and overexpression-specific effects. Related Articles | Metrics

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Polyphenols-gut microbiota interplay and brain neuromodulation Stefania Filosa, Francesco Di Meo, Stefania Crispi 2018, 13 (12):  2055-2059.  doi: 10.4103/1673-5374.241429 Abstract ( 130 )   PDF (269KB) ( 256 )   Save Increasing evidence suggests that food ingested polyphenols can have beneficial effects in neuronal protection acting against oxidative stress and inflammatory injury. Moreover, polyphenols have been reported to promote cognitive functions. Biotransformation of polyphenols is needed to obtain metabolites active in brain and it occurs through their processing by gut microbiota. Polyphenols metabolites could directly act as neurotransmitters crossing the blood-brain barrier or indirectly by modulating the cerebrovascular system. The microbiota-gut-brain axis is considered a neuroendocrine system that acts bidirectionally and plays an important role in stress responses. The metabolites produced by microbiota metabolism can modulate gut bacterial composition and brain biochemistry acting as neurotransmitters in the central nervous system. Gut microbiota composition can be influenced by dietary ingestion of natural bioactive molecules such as probiotics, prebiotics and polyphenol. Microbiota composition can be altered by dietary changes and gastrointestinal dysfunctions are observed in neurodegenerative diseases. In addition, several pieces of evidence support the idea that alterations in gut microbiota and enteric neuroimmune system could contribute to onset and progression of these age-related disorders. The impact of polyphenols on microbiota composition strengthens the idea that maintaining a healthy microbiome by modulating diet is essential for having a healthy brain across the lifespan. Moreover, it is emerging that they could be used as novel therapeutics to prevent brain from neurodegeneration. Related Articles | Metrics

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Ketogenic diet versus ketoacidosis: what determines the influence of ketone bodies on neurons? Sergei V. Fedorovich, Polina P. Voronina, Tatyana V. Waseem 2018, 13 (12):  2060-2063.  doi: 10.4103/1673-5374.241442 Abstract ( 203 )   PDF (237KB) ( 311 )   Save Glucose is the main energy substrate for neurons, however, at certain conditions, e.g. in starvation, these cells could also use ketone bodies. This approach is used in clinical conditions as the ketogenic diet. The ketogenic diet is actually a biochemical model of fasting. It includes replacing carbohydrates by fats in daily meal. Synthesis of ketone bodies β-hydroxubutirate, acetoacetate and acetone begins once glycogen stores have depleted in the liver. The ketogenic diet can be used to treat clinical conditions, primarily epilepsy. The mechanism of neuroprotective action of ketogenic diet is not very clear. It is shown that ketone bodies influence neurons at three different levels, namely, metabolic, signaling and epigenetic levels. Ketone bodies are not always neuroprotective. Sometimes they can be toxic for the brain. Ketoacidosis which is a very dangerous complication of diabetes mellitus or alcoholism can be taken as an example. The exact mechanism of how neuroprotective properties of ketone bodies reverse to neurotoxic is yet to be established. Related Articles | Metrics

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Apomorphine effects on the hippocampus Luis Enrique Arroyo-García, Antonio Rodríguez-Moreno, Gonzalo Flores 2018, 13 (12):  2064-2066.  doi: 10.4103/1673-5374.241443 Abstract ( 161 )   PDF (339KB) ( 291 )   Save Apomorphine is a non-specific dopamine receptor agonist that has been used in the treatment of some diseases and mental disorders. Its use has particularly well documented in Parkinson’s disease (PD). The dopaminergic agonists like apomorphine are related to oxidative processes that could induce cell damage and the functional impairment of some structures in the brain. However, most information about apomorphine in literature is focused on the improvement of the motor problems characteristic of PD, but little is known about the effects on cognitive behaviors and brain structures indirectly related to motor function. The presence of dopaminergic receptors in the hippocampus has recently been discovered, in connection with cognitive behaviors like learning and memory, these receptors are needed in neuronal plasticity. There has been a growing interest to know if this structure could be compromised by the effect of apomorphine and elucidate if part of the cognitive impairment present in the PD is due to the effect of apomorphine. In this mini-review, we summarized how apomorphine has been used since its creation, we discuss the latest information about its effect on the hippocampus and also the future perspectives to fully understand the effects of this compound. Related Articles | Metrics

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MicroRNAs of microglia: wrestling with central nervous system disease Xiao-Hua Wang, Tian-Long Wang 2018, 13 (12):  2067-2072.  doi: 10.4103/1673-5374.241444 Abstract ( 154 )   PDF (356KB) ( 252 )   Save Microglia serve as brain-resident myeloid cells that affect cerebral development, ischemia, neurodegeneration, and neuro-viral infection. MicroRNAs play a key role in central nervous system disease through post-transcriptional regulation. Indeed, evidence shows that microRNAs are one of the most important regulators mediating microglial activation, polarization, and autophagy, and subsequently affecting neuroinflammation and the outcome of central nervous system disease. In this review, we provide insight into the function of microRNAs, which may be an attractive strategy and influential treatment for microglia-related central nervous system dysfunction. Moreover, we comprehensively describe how microglia fight against central nervous system disease via multiple functional microRNAs. Related Articles | Metrics

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Inhibiting the kynurenine pathway in spinal cord injury: multiple therapeutic potentials? Kelly R. Jacobs, David B. Lovejoy 2018, 13 (12):  2073-2076.  doi: 10.4103/1673-5374.241446 Abstract ( 130 )   PDF (545KB) ( 274 )   Save Chronic induction of the kynurenine pathway (KP) contributes to neuroinflammation by producing the excitotoxin quinolinic acid (QUIN). This has led to significant interest in the development of inhibitors of this pathway, particularly in the context of neurodegenerative disease. However, acute spinal cord injury (SCI) also results in deleterious increases in QUIN, as secondary inflammatory processes mediated largely by infiltrating macrophages, become predominant. QUIN mediates significant neurotoxicity primarily by excitotoxic stimulation of the N-methyl-D-aspartate receptor, but other mechanisms of QUIN toxicity are known. More recent focus has assessed the contribution that neuroinflammation and modulations in the KP make in mood and psychiatric disorders with recent studies linking inflammation and modulations in the KP, to impaired cognitive performance and depressed mood in SCI patients. We hypothesize that these findings suggest that in SCI, inhibition of QUIN production and other metabolites, may have multiple therapeutic modalities and further studies investigating this are warranted. However, for central nervous system-based conditions, achieving good blood-brain-barrier permeability continues to be a limitation of current KP inhibitors. Related Articles | Metrics

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Is ATP a key player in conditioning neurons to support axonal regeneration? Xuenong Bo 2018, 13 (12):  2077-2079.  doi: 10.4103/1673-5374.241447 Abstract ( 133 )   PDF (458KB) ( 245 )   Save Neurons in the central nervous system (CNS) of adult mammals have a weak intrinsic regenerative capacity, which is one contributing factor to the failure of axonal regeneration. Finding the means to elevate the regenerative capacity of axotomised neurons is one requirement for successful regeneration. Forty-five years ago, it was reported that crushing of the sciatic nerves of adult mice two weeks before cutting the nerves accelerated the regrowth of their axons (McQuarrie and . The nerve injury two weeks before triggered the regeneration machinery in the injured neurons, leading to faster axonal regrowth after a subsequent lesion. Later it was found that a lesion to a peripheral nerve also strongly enhanced the regeneration of the central branches of the appropriate primary sensory neurons . This phenomenon is termed preconditioning lesion (or conditioning lesion if the central branches of the sensory neurons are injured after a concomitant injury to their peripheral branches). Conditioning lesion of peripheral nerves has been used in combination with other strategies in promoting sensory axon regeneration in injured spinal cord in animal models. Although conditioning lesion cannot be translated into clinical practice as intentional injury to the peripheral nerves of the patients would be counterproductive, studying the underlying molecular events will reveal how neurons respond to axonal injuries, leading to the development of practical therapeutic strategies for axonal regeneration. Related Articles | Metrics

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Role of chondroitin sulfate proteoglycan signaling in regulating neuroinflammation following spinal cord injury Scott M. Dyck, Soheila Karimi-Abdolrezaee 2018, 13 (12):  2080-2082.  doi: 10.4103/1673-5374.241452 Abstract ( 127 )   PDF (200KB) ( 240 )   Save Spinal cord injury (SCI) elicits a robust inflammatory response that is a hallmark of the secondary injury mechanisms. Neuroinflammation is orchestrated initially by the response of resident astrocytes and microglia to injury, which subsequently facilitates the recruitment of peripheral immune cells into the SCI lesion . This inflammatory response contributes to cell death and tissue degeneration through the production of pro-inflammatory cytokines and chemokines, free radicals and proteolytic enzymes. However, neuroinflammatory cells also play beneficial regulatory role in repair mechanisms after SCI by adopting a reparative and wound healing phenotype. Hence, understanding the underlying mechanisms by which immune cells are regulated within the microenvironment of injury would aid in harnessing the reparative potential of inflammation following SCI. Related Articles | Metrics

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Do new neurons contribute to functional reorganization after brain damage? Clorinda Arias, Angelica Zepeda 2018, 13 (12):  2083-2084.  doi: 10.4103/1673-5374.241448 Abstract ( 135 )   PDF (204KB) ( 220 )   Save The finding that adult neurogenesis occurs constitutively in the brain was a breakthrough in neuroscience and soon gained attention as a possible mechanism for neurorepair after brain damage. In a recent study we show that the dentate gyrus (DG) reorganizes anatomically over time after damage, while new neurons undergo maturation and activate in response to a contextual fear memory recall. These findings provide new evidence on the possible role of neurogenesis in cognitive recovery after brain injury. Related Articles | Metrics

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Emerging roles of the neural adaptor FE65 in neurite outgrowth Wen Li, Wai Wa Ray Chan, Jacky Chi Ki Ngo, Kwok-Fai Lau 2018, 13 (12):  2085-2086.  doi: 10.4103/1673-5374.241449 Abstract ( 162 )   PDF (410KB) ( 250 )   Save The brain is the third largest organ in the human body and consists of over 80 billion neurons. Neurons are interconnected by neurite to form a complex neural network that allows the communication of neurons to regulate different body functions and activities. Neurites, including axons and dendrites, are the projections of a neuron from the cell body. Dynamic neurite outgrowth is a fundamental neural process for the establishment and maintenance of the functional nervous system. Unfortunately, neurite damage is often observed after brain injuries and in the early stages of many neurodegenerative diseases and in case of age-related neural degeneration. However, stimulation of neurite regeneration has been a major challenge for brain regenerative medicine. For instance, the axon growth of neurons in the central nervous system (CNS) is suppressed by inhibitory molecules released from the neighboring injured cells such as myelin-associated glycoprotein, neurite outgrowth inhibitor-A, oligodendrocyte-myelin glycoprotein, and chondroitin sulfate proteoglycans. Unlike the neurons of the peripheral nervous system, which are capable of regenerating new growth cones (a specialized structure at the tip of the neurite for initiating neurite elongation) shortly after injuries, retraction bulbs are formed in the axons of injured CNS neurons that restrict the formation of proper connections between these neurons. Additionally, the regenerated axons need to grow across a considerable distance to bypass the areas of injury and consequently achieve reconnections. However, many processes that stimulate axon growth are switched off after brain development. Recent findings suggest that these developmental processes can be “re-activated.” Activating the intrinsic pathways for neurite outgrowth could potentially lead to axon regeneration in CNS neurons. Therefore, understanding the regulatory mechanisms of neurite outgrowth would not only advance our knowledge in brain development but also provide insights into methods of inducing neurite re-outgrowth after brain injuries and in the aftermath of neurodegenerative diseases. Related Articles | Metrics

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Role and limitations of rehabilitationinduced neural network remodeling after stroke Naohiko Okabe, Osamu Miyamoto 2018, 13 (12):  2087-2088.  doi: 10.4103/1673-5374.241450 Abstract ( 127 )   PDF (244KB) ( 221 )   Save There is plenty of evidence that proves the beneficial and reliable effects of rehabilitation therapy, making it the most common treatment for patients with chronic stroke. It is believed that rehabilitation improves functional recovery through neural network remodeling, which is observed as a motor map reorganization or functional connectivity change assessed by intracortical microstimulation or functional magnetic resonance imaging (MRI). This neural network remodeling results from morphological changes, such as dendritic arborization, axonal sprouting, and synapse formation in surviving neurons. Among the various neural networks, descending spinal pathways play a pivotal role in executing voluntary motor tasks since these pathways send motor commands generated from the motor cortex to the spinal cord, which directly controls muscle contraction. Thus, destruction of these pathways causes impairment of motor functions. Descending spinal pathways include direct pathways (e.g., corticospinal pathway) and indirect pathways (e.g., rubrospinal and reticulospinal pathways). While most studies have focused on the corticospinal pathway, both direct and indirect descending spinal pathways are known to be reorganized through axonal remodeling after stroke, to compensate the functional roles of the destroyed neural pathways. Axonal remodeling in these pathways can be promoted by therapeutic intervention including brain stimulation (e.g., direct current stimulation, optogenetic stimulation), blockade of growth inhibiting molecules (e.g., anti-NogoA immunotherapy, chondroitinase ABC), and rehabilitative therapy. Recently, we demonstrated that rehabilitation-induced axonal remodeling in the corticospinal pathway plays a significant role in functional recovery after stroke. Related Articles | Metrics

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Sarcopenia diagnosed using masseter muscle area predictive of early mortality following severe traumatic brain injury Rindi Uhlich, Parker Hu 2018, 13 (12):  2089-2090.  doi: 10.4103/1673-5374.241451 Abstract ( 132 )   PDF (161KB) ( 231 )   Save Traumatic brain injury (TBI) represents a global pandemic and is currently a leading cause of injury related death worldwide. Unfortunately, those who survive initial injury often suffer devastating functional, social, and economic consequences. Related Articles | Metrics

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Novel translational rat models of dopamine transporter deficiency Damiana Leo, Ilya Sukhanov, Raul R. Gainetdinov 2018, 13 (12):  2091-2093.  doi: 10.4103/1673-5374.241453 Abstract ( 119 )   PDF (327KB) ( 256 )   Save Dopamine (DA) is one of the brain’s fundamental neurotransmitters. Despite the fact that the dopaminergic synapses constitute less than 1% of all brain synapses, DA is implicated in a number of critical physiological functions and in the pathogenesis of important psychiatric diseases such as schizophrenia, attention-deficit/hyperactivity disorder (ADHD), Parkinson’s disease (PD) and others. Genetically modified animals represent important tools in understanding the role of DA in the regulation of brain functions and pathology. The most known transgenic animal models to investigate DA abnormalities are dopamine transporter (DAT) knock-out (KO) mice, DAT knock-down mice and DAT over-expressing mice. It is not surprising, since DAT (Slc6a3), the major target of psychostimulant drugs of abuse such as amphetamine (AMPH) and cocaine, plays a key role in maintaining both the extraneuronal and intraneuronal DA levels via selective re-uptake of released DA back in the presynaptic dopaminergic neurons. The data gained from studies using the transgenic mice have provided numerous advances in understanding not only basic principles of DA transmission, but also the mechanisms of psychotropic drugs action, interaction between neurotransmitter systems, pathological mechanisms involved in the DA-related brain disorders and uncovered new principles of therapy of these disorders. However, certain questions, particularly concerning the investigation of cognitive behavioural processes that are critical for modelling neuropsychiatric conditions can be more reliably addressed in transgenic rats. A rat has larger brain size for neurosurgery and electrophysiological recordings, richer behaviour and demonstrate more robust and reproducible performance in cognitive tasks . Thus, rats with deficient DAT function were developed by two groups independently. DAT-KO rat line from Leo and colleagues was created in outbred Wistar Han rats by using zinc finger nuclease technology. DAT-KO rats have no DAT protein and function due to the 5 bp deletion and an early stop codon insertion. DATN157K mutant rats from Vengeliene et al. were generated in an inbred F344 line by N-ethyl-N-nitrosourea (ENU)-induced spontaneous mutation. The rat DAT-N157K protein is transcribed and translated but is not correctly processed to the cell surface resulting in dramatically decreased (> 95%) of DAT function. Thus, by the level of DAT deficiency DATN157K mutant rats are more comparable to DAT knockdown, rather than DAT-KO mice. Since a well-known draw-back of the ENU technology is the induction of bystander mutations, DAT-N157K founder rats were backcrossed with intact female rats for up to 13 generations to reduce the chance of contribution of additional mutations to the observed phenotype. Related Articles | Metrics

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The rat model of placental ischemia as a model of postpartum posterior cortical atrophy? Ashtin B. Giambrone, Junie P. Warrington 2018, 13 (12):  2094-2095.  doi: 10.4103/1673-5374.241454 Abstract ( 95 )   PDF (273KB) ( 269 )   Save Potential link between preeclampsia (PE) and posterior cortical atrophy (PCA): PCA is a neurodegenerative disorder affecting the parietal, occipital, and occipital-temporal brain regions, often manifesting as a decline in visual processing and perception skills in affected individuals. The most common underlying pathology of PCA is Alzheimer’s disease, which disproportionally affects women. Indeed, approximately two-thirds of Alzheimer’s disease patients are women and some studies suggest that PCA is more common among women than men, although other studies report no sex differences in PCA incidence. Taken together, these findings point to the potential involvement of sex-specific factors such as pregnancy and pregnancy disorders like PE, in driving the increased risk of neurodegenerative diseases in women. While there are no studies showing a direct link between PE and PCA, a recent study reported decreased gray matter volume in the posterior brain region of women with a history of PE and subsequent late-life hypertension. Importantly, during pregnancy, not only do PE patients often present with visual symptoms but abnormal brain imaging findings are consistent most commonly with posterior cerebral or occipital lobe abnormalities, suggesting that PE-induced abnormalities occur most frequently in the posterior cerebrum. These findings support the hypothesis that women with a history of PE may be more likely to present with PCA later in life; however, no studies have specifically addressed this question. Furthermore, because of low awareness of the disorder, not much is known regarding the underlying pathophysiological mechanisms, and prevention and treatment strategies are lacking. A recent publication provided evidence that reduced utero-placental blood flow and resulting placental ischemia during pregnancy, led to neuroinflammation and increased water content in the posterior cortex at two months postpartum while other brain regions such as anterior cerebrum, striatum, and hippocampus were spared. Herein, we present that the rat model of placental ischemia may be a suitable tool to assess the underlying mechanisms of postpartum posterior cortical abnormalities. Related Articles | Metrics

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New models to study vulvodynia: hyperinnervation and nociceptor sensitization in the female genital tract Christine M. Barry, Kalyani K. Huilgol, Rainer V. Haberberger 2018, 13 (12):  2096-2097.  doi: 10.4103/1673-5374.241455 Abstract ( 158 )   PDF (161KB) ( 302 )   Save Vulvodynia is a prevalent form of chronic pain, most commonly affecting the vaginal vestibule (vestibulodynia) . Women with vulvodynia describe intense pain in response to light touch of the affected region, such that sexual function and other activities can be severely limited. Medical costs associated with vulvodynia are high, exceeding $21 billion annually in the United States. The high level of direct medical costs has been linked to high treatment failure rates. Many women with the disorder consult multiple practitioners and undergo multiple courses of treatment with limited benefit. Related Articles | Metrics

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Consequences of redefining Alzheimer’s disease in terms of amyloid burden without regard to cognitive decline Stephen R. Robinson, Holly M. Brothers, Maya L. Gosztyla 2018, 13 (12):  2098-2099.  doi: 10.4103/1673-5374.241456 Abstract ( 110 )   PDF (136KB) ( 302 )   Save Alzheimer’s disease (AD) redefined: For the past century, AD has been defined as a disease of progressive cognitive decline paired with a burden of amyloid-β (Aβ) plaques and pathologic tau tangles in the hippocampus and forebrain. However, a recent Framework paper jointly sponsored by the National Institute on Aging and the Alzheimer’s Association proposes new classification guidelines for AD, which, if adopted, will have profound consequences for the future management of AD. The new guidelines redefine AD in terms of the brain’s burdens of Aβ and to a lesser extent tau, regardless of cognitive status. This biological approach is consistent with other diseases (e.g., type 2 diabetes) that are defined and managed in terms of biomarkers, rather than on the basis of overt symptoms. This redefinition of AD is expected to greatly facilitate progress in clinical trials and therapeutics. Related Articles | Metrics

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Putative roles of cathepsin B in Alzheimer’s disease pathology: the good, the bad, and the ugly in one? Hans-Gert Bernstein, Gerburg Keilhoff 2018, 13 (12):  2100-2101.  doi: 10.4103/1673-5374.241457 Abstract ( 181 )   PDF (194KB) ( 260 )   Save Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder characterized by loss in memory, cognition, and executive function and activities of daily living. AD pathogenesis has been shown to involve loss of neurons and synapses, cholinergic deficits, amyloid-beta protein (Aβ) deposition, tau protein hyperphosphorylation, and neuroinflammation. Among the various cell pathologic events observed in AD, changes in Aβ metabolism proceed fastest, often preceding clinical symptoms. Since the detection of immunoreactive and enzymatically active cathepsin B (cathB; EC 3.4.22.1) in association with amyloid deposits there has been ongoing interest in possible functions of this lysosomal cysteine protease in AD, and intense research has been done during the past decades to learn more about the possible place of the enzyme in disease pathophysiology. Soon it became clear that cathB is not a bystander but an active player, which is prominently and in many ways involved in AD pathology. However, findings from different groups are controversial and confusing. We herein try to draw attention to the Janus-faced nature of cathB in AD, in that the enzyme may contribute to both neuroprotection and neurodegeneration. Although we have to acknowledge that human morally (good, bad) and aesthetic (ugly) categories are not really suitable to describe cell pathologic processes, we will use these terms to clearly separate studies showing “positive” (in the sense of lowering AD pathology) from those demonstrating “negative” (increasing AD pathology) properties of cathB in AD. References | Related Articles | Metrics

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Nose-to-brain drug delivery approach: a key to easily accessing the brain for the treatment of Alzheimer’s disease Amit Alexander, Shailendra Saraf 2018, 13 (12):  2102-2104.  doi: 10.4103/1673-5374.241458 Abstract ( 182 )   PDF (1780KB) ( 295 )   Save Alzheimer’s disease (AD): AD, a neurodegenerative disorder and a significant cause of dementia throughout the world mostly affects the older adults but sometimes also seen in young age (early state AD). As per the Alzheimer Association report 2017, AD remains to be considered as the 6th leading cause of death which nearly touches around 5.5 million people only in the USA and the data is similar throughout the world (approximately 37 million people suffers from AD). On the other hand, the treatments are insufficient, and the available therapies do not claim the complete cure of disease. Instead, they relieve the symptoms in the preliminary stage. Also, AD therapies are very costly, mostly unaffordable for an average income population. Such constraint is due to the inaccessibility of the brain. The human brain is the most complex and delicate organ, highly protected by various physiological shields primarily the blood-brain-barrier (BBB). The BBB upholds the homeostasis of the brain and restricts the entry of most of the foreign components including lipids, peptides, and essential nutrients. Thus, the entry of almost all the drugs and bioactive to the brain remains complicated. The intranasal (IN) route offers an alternative approach for drug delivery to the brain without the interference of the BBB. In our previous article, we have discussed various innovative approaches, describing the novel techniques, efficiency, limitations, clinical investigations, patents, FDA status, current scenario and future possibilities of direct noseto-brain drug delivery. Related Articles | Metrics

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Cell-based therapy in Alzheimer’s disease: can human fetal cholinergic neurons “untangle the skein”? Giulia Guarnieri, Erica Sarchielli, Gabriella B. Vannelli, Annamaria Morelli 2018, 13 (12):  2105-2107.  doi: 10.4103/1673-5374.241459 Abstract ( 123 )   PDF (2022KB) ( 286 )   Save Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common form of old-age dementia. The disease is characterized by a progressive decline in cognitive functions, gradual loss of memory and ability to perform everyday activities, and leads to inevitable death within 3 to 9 years after diagnosis. The pathological hallmarks of the disease are the accumulation of intracellular neurofibrillary tangles, composed of the microtubule associated protein tau, and extracellular deposits of amyloid-β (Aβ) plaques, which are overall responsible for an extensive loss of neurons and synaptic connectivity. Related Articles | Metrics

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Peptide aptamer-mediated modulation of prion protein α-cleavage as treatment strategy for prion and other neurodegenerative diseases Antonia N. Klein, Erica Corda, Sabine Gilch 2018, 13 (12):  2108-2110.  doi: 10.4103/1673-5374.241460 Abstract ( 112 )   PDF (433KB) ( 255 )   Save Despite intensive research, most neurodegenerative diseases cannot be cured and for some of them no treatment is available to increase survival or quality of life. Among the latter are prion diseases, fatal and transmissible neurodegenerative diseases of humans and other animals. Examples are Creutzfeldt-Jakob disease (CJD) in man, bovine spongiform encephalopathy (BSE, also known as mad cow disease) in cattle, scrapie in sheep and goats, and chronic wasting disease (CWD) in cervids. Most human prion diseases manifest sporadically, but also genetic and infectious origins are known. Prions, the causal agent of prion diseases, are composed solely of protein, namely a misfolded isoform of the cellular prion protein PrPC, termed PrPSc. They are transmissible within and between species. Human-to-human transmission can occur through medical procedures (e.g.,neurosurgery) and results in iatrogenic CJD (iCJD). The largest number of iCJD cases worldwide has been reported upon treating growth hormone deficits with prion-contaminated cadaveric pituitary-derived human growth hormones. Transmission of BSE from cows to humans is to date the only example of zoonotic prion transmission resulting in variant CJD. Whether CWD is transmissible to humans is unknown but represents a current threat due to expansion of geographic distribution within and beyond North America and in light of a novel study indicating oral transmission to non-human primates. In this context, finding a treatment against prion disease is of primary importance. Related Articles | Metrics

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2-(2-Benzofuranyl)-2-imidazoline treatment within 5 hours after cerebral ischemia/reperfusion protects the brain Zheng Zhang, Jin-Long Yang, Lin-Lei Zhang, Zhen-Zhen Chen, Jia-Ou Chen, Yun-Gang Cao, Man Qu, Xin-Da Lin, Xun-Ming Ji, Zhao Han 2018, 13 (12):  2111-2118.  doi: 10.4103/1673-5374.241461 Abstract ( 111 )   PDF (3543KB) ( 310 )   Save We previously demonstrated that administering 2-(2-benzofuranyl)-2-imidazolin (2-BFI), an imidazoline I2 receptor agonist, immediately after ischemia onset can protect the brain from ischemic insult. However, immediate administration after stroke is difficult to realize in the clinic. Thus, the therapeutic time window of 2-BFI should be determined. Sprague-Dawley rats provided by Wenzhou Medical University in China received right middle cerebral artery occlusion for 120 minutes, and were treated with 2-BFI (3 mg/kg) through the caudal vein at 0, 1, 3, 5, 7, and 9 hours after reperfusion. Neurological function was assessed using the Longa’s method. Infarct volume was measured by 2,3,5-triphenyltetrazolium chloride assay. Morphological changes in the cortical penumbra were observed by hematoxylin-eosin staining under transmission electron microscopy . The apoptosis levels in the ipsilateral cortex were examined with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The protein expression of Bcl-2 and BAX was detected using immunohistochemistry. We found the following: Treatment with 2-BFI within 5 hours after reperfusion obviously improved neurological function. Administering 2-BFI within 9 hours after ischemia/reperfusion decreased infarct volume and alleviated apoptosis. 2-BFI administration at different time points after reperfusion alleviated the pathological damage of the ischemic penumbra and reduced the number of apoptotic neurons, but the protective effect was more obvious when administered within 5 hours. Administration of 2-BFI within 5 hours after reperfusion remarkably increased Bcl-2 expression and decreased BAX expression. To conclude, 2-BFI shows potent neuroprotective effects when administered within 5 hours after reperfusion, seemingly by up-regulating Bcl-2 and down-regulating BAX expression. The time window provided clinical potential for ischemic stroke by 2-BFI. Related Articles | Metrics

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Rosmarinic acid elicits neuroprotection in ischemic stroke via Nrf2 and heme oxygenase 1 signaling Hai-Ying Cui, Xiang-Jian Zhang, Yi Yang, Cong Zhang, Chun-Hua Zhu, Jiang-Yong Miao, Rong Chen 2018, 13 (12):  2119-2128.  doi: 10.4103/1673-5374.241463 Abstract ( 198 )   PDF (2868KB) ( 315 )   Save Rosmarinic acid (RA) can elicit a neuroprotective effect against ischemic stroke, but the precise molecular mechanism remains poorly understood. In this study, an experimental ischemic stroke model was established in CD-1 mice (Beijing Vital River Laboratory Animal Technology, Beijing, China) by occluding the right middle cerebral artery for 1 hour and allowing reperfusion for 24 hours. After intraperitoneally injecting model mice with 10, 20, or 40 mg/kg RA, functional neurological deficits were evaluated using modified Longa scores. Subsequently, cerebral infarct volume was measured using TTC staining and ischemic brain tissue was examined for cell apoptosis with TUNEL staining. Superoxide dismutase activity and malondialdehyde levels were measured by spectrophometry. Expression of heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), Bcl-2, Bax, Akt, and phospho-Ser473 Akt proteins in ischemic brain tissue was detected by western blot, while mRNA levels of Nrf2, HO-1, Bcl-2, and Bax were analyzed using real time quantitative PCR. In addition, HO-1 enzyme activity was measured spectrophotometrically. RA (20 and 40 mg/kg) greatly improved neurological function, reduced infarct volume, decreased cell apoptosis, upregulated Bcl-2 protein and mRNA expression, downregulated Bax protein and mRNA expression, increased HO-1 and Nrf2 protein and mRNA expression, increased superoxide dismutase activity, and decreased malondialdehyde levels in ischemic brain tissue of model mice. However, intraperitoneal injection of a HO-1 inhibitor (10 mg/kg zinc protoporphyrin IX) reversed the neuroprotective effects of RA on HO-1 enzyme activity and Bcl-2 and Bax protein expression. The PI3K/Akt signaling pathway inhibitor LY294002 (10 mM) inhibited Akt phosphorylation, as well as Nrf2 and HO-1 expression. Our findings suggest that RA has anti-oxidative and anti-apoptotic properties that protect against ischemic stroke by a mechanism involving upregulation of Nrf2 and HO-1 expression via the PI3K/Akt signaling pathway. Related Articles | Metrics

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Neuroprotective effect of baicalin on focal cerebral ischemia in rats Jiong Dai, Yong-Ming Qiu, Zheng-Wen Ma, Guo-Feng Yan, Jing Zhou, Shan-Quan Li, Hui Wu, Yi-Chao Jin, Xiao-Hua Zhang 2018, 13 (12):  2129-2133.  doi: 10.4103/1673-5374.241464 Abstract ( 154 )   PDF (1124KB) ( 239 )   Save Baicalin, a flavonoid compound from the root of the herb Scutellaria baicalensis Georgi, has been widely used to treat patients with inflammatory disease. The aim of this study was to assess the efficacy of baicalin in a rat model of focal cerebral ischemia. Adult male Sprague-Dawley rat models of cerebral artery occlusion were established and then randomly and equally divided into three groups: ischemia (cerebral ischemia and reperfusion), valproic acid (cerebral ischemia and reperfusion + three intraperitoneal injections of valproic acid; positive control), and baicalin (cerebral ischemia and reperfusion + intraperitoneal injection of baicalin for 21 days). Neurological deficits were assessed using the postural reflex test and forelimb placing test at 3, 7, 14, and 21 days after ischemia. Rat cerebral infarct volume was measured using 2,3,5-triphenyltetrazolium chloride (TTC) staining method. Pathological change of ischemic brain tissue was assessed using hematoxylin-eosin staining. In the baicalin group, rat neurological function was obviously improved, cerebral infarct volume was obviously reduced, and the pathological impairment of ischemic brain tissue was obviously alleviated compared to the ischemia group. Cerebral infarct volume was similar in the valproic acid and baicalin groups. These findings suggest that baicalin has a neuroprotective effect on cerebral ischemia. Related Articles | Metrics

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Dynamic changes in growth factor levels over a 7-day period predict the functional outcomes of traumatic brain injury Shuai Zhou, Dong-Pei Yin, Yi Wang, Ye Tian, Zeng-Guang Wang, Jian-Ning Zhang 2018, 13 (12):  2134-2140.  doi: 10.4103/1673-5374.241462 Abstract ( 134 )   PDF (623KB) ( 260 )   Save Traumatic brain injury (TBI) can result in poor functional outcomes and death, and overall outcomes are varied. Growth factors, such as angiopoietin-1 (Ang-1), vascular endothelial growth factor (VEGF), and granulocyte-colony stimulating factor (G-CSF), play important roles in the neurological functions. This study investigated the relationship between serum growth factor levels and long-term outcomes after TBI. Blood samples from 55 patients were collected at 1, 3 and 7 days after TBI. Blood samples from 39 healthy controls were collected as a control group. Serum Ang-1, G-CSF, and VEGF levels were measured using ELISA. Patients were monitored for 3 months using the Glasgow Outcome Scale-Extended (GOSE). Patients having a GOSE score of > 5 at 3 months were categorized as a good outcome, and patients with a GOSE score of 1–5 were categorized as a bad outcome. Our data demonstrated that TBI patients showed significantly increased growth factor levels within 7 days compared with healthy controls. Serum levels of Ang-1 at 1 and 7 days and G-CSF levels at 7 days were significantly higher in patients with good outcomes than in patients with poor outcomes. VEGF levels at 7 days were remarkably higher in patients with poor outcomes than in patients with good outcomes. Receiver operating characteristic analysis showed that the best cut-off points of serum growth factor levels at 7 days to predict functional outcome were 1,333 pg/mL for VEGF, 447.2 pg/mL for G-CSF, and 90.6 ng/mL for Ang-1. These data suggest that patients with elevated levels of serum Ang-1, G-CSF, and decreased VEGF levels had a better prognosis in the acute phase of TBI (within 7 days). This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800018251) on September 7, 2018. Related Articles | Metrics

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Prevalence of white matter hyperintensities increases with age Feng-Juan Zhuang, Yan Chen, Wen-Bo He, Zhi-You Cai 2018, 13 (12):  2141-2146.  doi: 10.4103/1673-5374.241465 Abstract ( 269 )   PDF (340KB) ( 257 )   Save White matter hyperintensities (WMHs) that arise with age and/or atherosclerosis constitute a heterogeneous disorder in the white matter of the brain. However, the relationship between age-related risk factors and the prevalence of WMHs is still obscure. More clinical data is needed to confirm the relationship between age and the prevalence of WMHs. We collected 836 patients, who were treated in the Renmin Hospital, Hubei University of Medicine, China from January 2015 to February 2016, for a case-controlled retrospective analysis. According to T2-weighted magnetic resonance imaging results, all patients were divided into a WMHs group (n = 333) and a non-WMHs group (n = 503). The WMHs group contained 159 males and 174 females. The prevalence of WMHs increased with age and was associated with age-related risk factors, such as cardiovascular diseases, smoking, drinking, diabetes, hypertension and history of cerebral infarction. There was no significant difference in sex, education level, hyperlipidemia and hyperhomocysteinemia among the different age ranges. These findings confirm that age is an independent risk factor for the prevalence and severity of WMHs. The age-related risk factors enhance the occurrence of WMHs. Related Articles | Metrics

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Downregulation of signal transduction and STAT3 expression exacerbates oxidative stress mediated by NLRP3 inflammasome Hua Bai, Qi-Fang Zhang, Juan-Juan Duan, De-Jun Yu, Li-Jie Liu 2018, 13 (12):  2147-2155.  doi: 10.4103/1673-5374.241470 Abstract ( 130 )   PDF (507KB) ( 252 )   Save Activated nucleotide binding to the oligonucleotide receptor protein 3 (NLRP3) inflammasome is possibly involved in the pathogenesis of Alzheimer’s disease through oxidative stress and neurogenic inflammation. Low expression of the signal transducer and activator of transcription 3 (STAT3) gene may promote the occurrence of neurodegenerative diseases to some extent. To clarify the roles of the NLRP3 inflammasome and STAT3 expression in oxidative stress, (1) SHSY5Y cells were incubated with 1 mM H2O2 to induce oxidative stress injury, and the expression of human-cell-specific signal transduction, STAT3-shRNA silencing signal transduction and STAT3 were detected. Cells were pretreated with Ca2+ chelator BAPATA-AM (0.1 mM) for 30 minutes as a control. (2) Western blot assay was used to analyze the expression of caspase-1, NLRP3, signal transduction and STAT3. Enzyme-linked immunosorbent assay was used to analyze interleukin-1β levels. Flow cytometry was carried out to calculate the number of apoptotic cells. We found that H2O2 treatment activated NLRP3 inflammasomes and decreased phosphorylation of signal transduction and STAT3 serine 727. BAPTA-AM pretreatment abolished the H2O2-induced activation of NLRP3 inflammasomes, caspase-1 expression, interleukin-1β expression and apoptosis in SHSY5Y cells, and had no effect in cells with downregulated STAT3 expression by RNAi. The findings suggest that downregulation of signal transduction and STAT3 expression may enhance the oxidative stress mediated by NLRP3, which may not depend on the Ca2+ signaling pathway. Related Articles | Metrics

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Dysphagia in patients with isolated pontine infarction Min Cheol Chang, Sang Gyu Kwak, Min Ho Chun 2018, 13 (12):  2156-2159.  doi: 10.4103/1673-5374.241466 Abstract ( 143 )   PDF (181KB) ( 266 )   Save Little is known about dysphagia after pontine infarction. In this study, we evaluated the incidence of dysphagia after isolated pontine infarction and identified the predictive factors for the occurrence of dysphagia. A total of 146 patients were included in this study. All patients underwent clinical testing for dysphagia within 1 day after admission and at the time of discharge. We compared the incidence of dysphagia between patients with unilateral pontine infarction and those with bilateral pontine infarction. To evaluate the functional status of patients, we investigated their initial modified Rankin Scale (mRS) score and initial National Institutes of Health Stroke Scale (NIHSS) score within 1 day of admission. Of 146 patients, 50 (34.2%) had dysphagia initially within 1 day after admission. At the second evaluation at the time of discharge, dysphagia was diagnosed in 24 patients (16.4%). Patients with bilateral pontine infarction were more likely to present with dysphagia. In addition, clinical severity (in terms of mRS and NIHSS scores) was identified as a predictor of dysphagia in patients with cerebral infarction (multiple binary logistic regression analysis, mRS: P = 0.011, NIHSS: P = 0.004). Dysphagia frequently occurs in patients with isolated pontine infarction. Clinicians should pay particular attention to the occurrence of dysphagia, especially in patients with bilateral pontine infarction or high functional disability. Related Articles | Metrics

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Epigenetic marks are modulated by gender and time of the day in the hippocampi of adolescent rats: a preliminary study Viviane Rostirola Elsner, Laura Reck Cechinel, Louisiana Carolina Ferreira de Meireles, Karine Bertoldi, Ionara Rodrigues Siqueira 2018, 13 (12):  2160-2163.  doi: 10.4103/1673-5374.241467 Abstract ( 134 )   PDF (213KB) ( 203 )   Save Although the involvement of gender in epigenetic machinery in peripheral tissues during the neonatal period has been suggested, the gender-related epigenetic profile of brain areas during the adolescent period is rarely exploited. Furthermore, the influence of time of day on hippocampal acetylation marks has been demonstrated in young adult and aged rats; however, there are no studies reporting epigenetic changes in the adolescent period. Therefore, this study aimed to investigate the effects of gender on hippocampal DNA methyltransferase 1 content and histone deacetylase (HDAC) activity of adolescent rats at different time points, specifically early morning and afternoon. Both epigenetic markers increased significantly in the hippocampi of female rats compared to the male group, an indicator of reduced transcriptional activity. In addition, HDAC activity during the early morning was higher compared to afternoon groups in both male and female rats, while DNA methyltransferase 1 content was not altered by the time of day. Our findings demonstrate that hippocampal DNA methylation and histone acetylation status can be influenced by gender during the adolescent period, while the time of the day impacts HDAC activity. Related Articles | Metrics

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Partial improvement in performance of patients with severe Alzheimer’s disease at an early stage of fornix deep brain stimulation Zhi-Qi Mao, Xin Wang, Xin Xu, Zhi-Qiang Cui, Long-Sheng Pan, Xiao-Jing Ning, Bai-Xuan Xu, Lin Ma, Zhi-Pei Ling, Jian-Jun Jia, Xin-Guang Yu 2018, 13 (12):  2164-2172.  doi: 10.4103/1673-5374.241468 Abstract ( 161 )   PDF (652KB) ( 325 )   Save Deep brain stimulation is a therapy for Alzheimer’s disease (AD) that has previously been used for mainly mild to moderate cases. This study provides the first evidence of early alterations in performance induced by stimulation targeted at the fornix in severe AD patients. The performance of the five cases enrolled in this study was scored with specialized assessments including the Mini-Mental State Examination and Clinical Dementia Rating, both before and at an early stage after deep brain stimulation. The burden of caregivers was also evaluated using the Zarit Caregiver Burden Interview. As a whole, the cognitive performance of patients remained stable or improved to varying degrees, and caregiver burden was decreased. Individually, an improved mental state or social performance was observed in three patients, and one of these three patients showed remarkable improvement in long-term memory. The conditions of another patient deteriorated because of inappropriate antipsychotic medications that were administered by his caregivers. Taken together, deep brain stimulation was capable of improving some cognitive aspects in patients with severe AD, and of ameliorating their emotional and social performance, at least at an early stage. However, long-term effects induced by deep brain stimulation in patients with severe AD need to be further validated. More research should focus on clarifying the mechanism of deep brain stimulation. This study was registered with ClinicalTrials.gov (NCT03115814) on April 14, 2017. Related Articles | Metrics

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Exogenous brain-derived neurotrophic factor attenuates cognitive impairment induced by okadaic acid in a rat model of Alzheimer’s disease Ai-Hua Xu, Yang Yang, Yong-Xin Sun, Chao-Dong Zhang 2018, 13 (12):  2173-2181.  doi: 10.4103/1673-5374.241471 Abstract ( 130 )   PDF (1815KB) ( 257 )   Save Decreased expression of brain-derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of Alzheimer’s disease, and a typical pathological change in Alzheimer’s disease is neurofibrillary tangles caused by hyperphosphorylation of tau. An in vivo model of Alzheimer’s disease was developed by injecting okadaic acid (2 μL) and exogenous BDNF (2 μL) into the hippocampi of adult male Wister rats. Spatial learning and memory abilities were assessed using the Morris water maze. The expression levels of protein phosphatase 2A (PP2A), PP2Ac-Yp307, p-tau (Thr231), and p-tau (Ser396/404) were detected by western blot assay. The expression levels of BDNF, TrkB, and synaptophysin mRNA were measured by quantitative real-time polymerase chain reaction. Our results indicated that BDNF expression was suppressed in the hippocampus of OA-treated rats, which resulted in learning and memory deficits. Intra-hippocampal injection of BDNF attenuated this OA-induced cognitive impairment. Finally, our findings indicated an involvement of the PI3K/GSK-3β/AKT pathway in the mechanism of BDNF in regulating cognitive function. These results indicate that BDNF has beneficial effect on Alzheimer’s disease, and highlight the potential of BDNF as a drug target for treatment of Alzheimer’s disease. Related Articles | Metrics

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Analysis of transcriptome sequencing of sciatic nerves in Sprague-Dawley rats of different ages Jiang-Hui Liu, Qing Tang, Xiang-Xia Liu, Jian Qi, Rui-Xi Zeng, Zhao-Wei Zhu, Bo He, Yang-Bin Xu 2018, 13 (12):  2182-2190.  doi: 10.4103/1673-5374.241469 Abstract ( 202 )   PDF (1660KB) ( 2537 )   Save An aging-induced decrease in Schwann cell viability can affect regeneration following peripheral nerve injury in mammals. It is therefore necessary to investigate possible age-related changes in gene expression that may affect the biological function of peripheral nerves. Ten 1-week-old and ten 12-month-old healthy male Sprague-Dawley rats were divided into young (1 week old) and adult (12 months old) groups according to their ages. mRNA expression in the sciatic nerve was compared between young and adult rats using next-generation sequencing (NGS) and bioinformatics (n = 4/group). The 18 groups of differentially expressed mRNA (DEmRNAs) were also tested by quantitative reverse transcription polymerase chain reaction (n = 6/group). Results revealed that (1) compared with young rats, adult rats had 3608 groups of DEmRNAs. Of these, 2684 were groups of upregulated genes, and 924 were groups of downregulated genes. Their functions mainly involved cell viability, proliferation, differentiation, regeneration, and myelination. (2) The gene with the most obvious increase of all DEmRNAs in adult rats was Thrsp (log2FC = 9.01, P < 0.05), and the gene with the most obvious reduction was Col2a1 (log2FC = –8.89, P < 0.05). (3) Gene Ontology analysis showed that DEmRNAs were mainly concentrated in oligosaccharide binding, nucleotide-binding oligomerization domain containing one signaling pathway, and peptide-transporting ATPase activity. (4) Analysis using the Kyoto Encyclopedia of Genes and Genomes showed that, with increased age, DEmRNAs were mainly enriched in steroid biosynthesis, Staphylococcus aureus infection, and graft-versus-host disease. (5) Spearman’s correlation coefficient method for evaluating NGS accuracy showed that the NGS results and quantitative reverse transcription polymerase chain reaction results were positively correlated (rs = 0.74, P < 0.05). These findings confirm a difference in sciatic nerve gene expression between adult and young rats, suggesting that, in peripheral nerves, cells and the microenvironment change with age, thus influencing the function and repair of peripheral nerves. Related Articles | Metrics

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Lithium promotes recovery of neurological function after spinal cord injury by inducing autophagy Duo Zhang, Fang Wang, Xu Zhai, Xiao-Hui Li, Xi-Jing He 2018, 13 (12):  2191-2199.  doi: 10.4103/1673-5374.241473 Abstract ( 180 )   PDF (3374KB) ( 299 )   Save Lithium promotes autophagy and has a neuroprotective effect on spinal cord injury (SCI); however, the underlying mechanisms remain unclear. Therefore, in this study, we investigated the effects of lithium and the autophagy inhibitor 3-methyladenine (3-MA) in a rat model of SCI. The rats were randomly assigned to the SCI, lithium, 3-MA and sham groups. In the 3-MA group, rats were intraperitoneally injected with 3-MA (3 mg/kg) 2 hours before SCI. In the lithium and 3-MA groups, rats were intraperitoneally injected with lithium (LiCl; 30 mg/kg) 6 hours after SCI and thereafter once daily until sacrifice. At 2, 3 and 4 weeks after SCI, neurological function and diffusion tensor imaging indicators were remarkably improved in the lithium group compared with the SCI and 3-MA groups. The Basso, Beattie and Bresnahan locomotor rating scale score and fractional anisotropy values were increased, and the apparent diffusion coefficient value was decreased. Immunohistochemical staining showed that immunoreactivities for Beclin-1 and light-chain 3B peaked 1 day after SCI in the lithium and SCI groups. Immunoreactivities for Beclin-1 and light-chain 3B were weaker in the 3-MA group than in the SCI group, indicating that 3-MA inhibits lithium-induced autophagy. Furthermore, NeuN+ neurons were more numerous in the lithium group than in the SCI and 3-MA groups, with the fewest in the latter. Our findings show that lithium reduces neuronal damage after acute SCI and promotes neurological recovery by inducing autophagy. The neuroprotective mechanism of action may not be entirely dependent on the enhancement of autophagy, and furthermore, 3-MA might not completely inhibit all autophagy pathways. Related Articles | Metrics

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Huangqin flavonoid extraction for spinal cord injury in a rat model Qian Zhang, Li-Xin Zhang, Jing An, Liang Yan, Cui-Cui Liu, Jing-Jing Zhao, Hao Yang 2018, 13 (12):  2200-2208.  doi: 10.4103/1673-5374.241472 Abstract ( 102 )   PDF (2134KB) ( 331 )   Save Flavonoids from Huangqin (dried roots of Scutellaria baicalensis Georgi) have anti-inflammatory effects, and are considered useful for treatment of spinal cord injury. To verify this hypothesis, the T9–10 spinal cord segments of rats were damaged using Allen’s method to establish a rat spinal cord injury model. Before model establishment, Huangqin flavonoid extraction (12.5 g/kg) was administered intragastrically for 1 week until 28 days after model establishment. Methylprednisolone (30 mg/kg) was injected into the tail vein at 30 minutes after model establishment as a positive control. Basso, Beattie, and Bresnahan locomotor scale scores were used to assess hind limb motor function. Hematoxylin-eosin staining was used to detect pathological changes in the injured spinal cord. Immunofluorescence and western blot assays were performed to measure immunoreactivity and expression levels of brain-derived neurotrophic factor, neuronal marker neurofilament protein, microglial marker CD11b and astrocyte marker glial fibrillary acidic protein in the injured spinal cord. Huangqin flavonoid extraction markedly reduced spinal cord hematoma, inflammatory cell infiltration and cavities and scars, and increased the Basso, Beattie, and Bresnahan locomotor scale scores; these effects were identical to those of methylprednisolone. Huangqin flavonoid extraction also increased immunoreactivity and expression levels of brain-derived neurotrophic factor and neurofilament protein, and reduced immunoreactivity and expression levels of CD11b and glial fibrillary acidic protein, in the injured spinal cord. Overall, these data suggest that Huangqin flavonoid extraction can promote recovery of spinal cord injury by inducing brain-derived neurotrophic factor and neurofilament protein expression, reducing microglia activation and regulating reactive astrocytes. Related Articles | Metrics