Restore Brain Function Research Articles

α7 Nicotinic Receptor Agonist Enhances Cognition in Aged 3xTg-AD Mice with Robust Plaques and Tangles

Alzheimer disease (AD) is a progressive neurodegenerative disorder with associated memory loss, spatial disorientation, and other psychiatric problems. Cholinergic system dysfunction is an early and salient feature of AD, and enhancing cholinergic signaling with acetylcholinesterase inhibitors is currently the primary strategy for improving cognition. The beneficial effects of acetylcholinesterase inhibitors, however, are typically short-lived and accompanied by adverse effects. Recent evidence suggests that activating α7 nicotinic acetylcholine receptors (α7 nAChR) may facilitate the specific modulation of brain cholinergic signaling, leading to cognitive enhancement and possibly to amelioration of AD pathologic findings. In the present study, we determined the effect of long-term treatment with the selective α7 nAChR agonist A-582941 in aged 3xTg-AD mice with robust AD-like pathology, which is particularly significant not only because this is the only mouse model that co-develops amyloid plaques and neurofibrillary tangles but also because it enabled us to explore whether A-582941 is able to restore brain function after the severe damage associated with AD. Analysis of β-amyloid deposits, tau phosphorylation, and inflammatory cells revealed that, overall, pathologic findings were unchanged. Rather, α7 nAChR activation induced expression of c-Fos and brain-derived neurotrophic factor and phosphorylation of cyclic adenosine monophosphate response element binding and neurotrophic tyrosine receptor kinase type 2. More important, A-582941 completely restored cognition in aged 3xTg-AD mice to the level of that in age-matched nontransgenic mice. These novel findings indicate that activating α7 nAChR is a promising treatment for cognitive impairment in AD.

Unique Mechanisms of Sheng Yu Decoction (聖愈湯 Shèng Yù Tang) on Ischemic Stroke Mice Revealed by an Integrated Neurofunctional and Transcriptome Analysis

Sheng Yu Decoction (聖愈湯 Shèng Yù Tang; SYD) is a popular traditional Chinese medicine (TCM) remedy used in treating cardiovascular and brain-related dysfunction clinically; yet, its neuroprotective mechanisms are still unclear. Here, mice were subjected to an acute ischemic stroke to examine the efficacy and mechanisms of action of SYD by an integrated neurofunctional and transcriptome analysis. More than 80% of the mice died within 2 days after ischemic stroke with vehicle treatment. Treatments with SYD (1.0 g/kg, twice daily, orally or p.o.) and recombinant thrombolytic tissue plasminogen activator (rt-PA; 10 mg/kg, once daily, intravenously or i.v.) both significantly extended the lifespan as compared to that of the vehicle-treated stroke group. SYD successfully restored brain function, ameliorated cerebral infarction and oxidative stress, and significantly improved neurological deficits in mice with stroke. Molecular impact of SYD by a genome-wide transcriptome analysis using brains from stroke mice showed a total of 162 out of 2081 ischemia-induced probe sets were significantly influenced by SYD. Mining the functional modules and genetic networks of these 162 genes revealed a significant upregulation of neuroprotective genes in Wnt receptor signaling pathway (3 genes) and regulation of cell communication (7 genes) and downregulation of destructive genes in response to stress (13 genes) and in the induction of inflammation (5 genes), cytokine production (4 genes), angiogenesis (3 genes), vasculature (6 genes) and blood vessel (5 genes) development, wound healing (7 genes), defense response (7 genes), chemotaxis (4 genes), immune response (7 genes), antigen processing and presenting (3 genes), and leukocyte-mediated cytotoxicity (2 genes) by SYD. Our results suggest that SYD could protect mice against ischemic stroke primarily through significantly downregulating the damaging genes involved in stress, inflammation, angiogenesis, blood vessel formation, immune responses, and wound healing, as well as upregulating the genes mediating neurogenesis and cell communication, which make SYD beneficial for treating ischemic stroke.

The Endogenous Regenerative Capacity of the Damaged Newborn Brain: Boosting Neurogenesis with Mesenchymal Stem Cell Treatment

Neurogenesis continues throughout adulthood. The neurogenic capacity of the brain increases after injury by, e.g., hypoxia-ischemia. However, it is well known that in many cases brain damage does not resolve spontaneously, indicating that the endogenous regenerative capacity of the brain is insufficient. Neonatal encephalopathy leads to high mortality rates and long-term neurologic deficits in babies worldwide. Therefore, there is an urgent need to develop more efficient therapeutic strategies. The latest findings indicate that stem cells represent a novel therapeutic possibility to improve outcome in models of neonatal encephalopathy. Transplanted stem cells secrete factors that stimulate and maintain neurogenesis, thereby increasing cell proliferation, neuronal differentiation, and functional integration. Understanding the molecular and cellular mechanisms underlying neurogenesis after an insult is crucial for developing tools to enhance the neurogenic capacity of the brain. The aim of this review is to discuss the endogenous capacity of the neonatal brain to regenerate after a cerebral ischemic insult. We present an overview of the molecular and cellular mechanisms underlying endogenous regenerative processes during development as well as after a cerebral ischemic insult. Furthermore, we will consider the potential to use stem cell transplantation as a means to boost endogenous neurogenesis and restore brain function.

Tetramethylpyrazine protects brain function from severe brain injury in patients: quantitative research

Objective To investigate the effect of Tetramethylpyrazine (extracted from Chinese herbal medicine Ligusticum wallichii) employed in the early stage of severe brain injury on the restoration of brain function in coma patients monitored with digitized cerebral state monitor and clinical signs.Methods A total of 364 patients were referred to us from Emergency Department and Neurosurgery Department,Shenzhen People's Hospital from January 2006 through May 2012.The scores of patients'GlasgowPittsburgh coma scales were between 7-20 as brain injury happened within 24 h and survived more than two weeks.All patients were randomly (random number) divided into two groups:Tetramethylpyrazine group (n =186) and control group (n =178).The patients of control group received routine treatment,and the patients of Tetramethylpyrazine group were treated with Tetramethylpyrazine in addition to routine treatment in early stage.The patients of two groups were assessed with cerebral state indexes (CSI) and GlasgowPittsburgh coma scales before treatment and 3,7,14 days after treatment.Statistical comparisons between groups were analyzed by using repeated measure design analysis of variance.Results A repeated measures design analysis of variance indicated that the CSI and clinical signs (Glasgow-Pittsburgh coma scale) were improved significantly in Tetramethylpyrazine group than those in the control group at 3,7,14 days after treatment (P =0.024).Conclusions Tetramethylpyrazine can protect brain function and improve clinical signs in patients with severe brain injury in the early stage. Key words: Tetramethylpyrazine; Cerebral injury ; Cerebral function ; Monitor

Brain restoration as an emerging field in neurology and neuroscience

Restoration of brain function was long thought to be impossible. However, as the publications in the journal Restorative Neurology and Neuroscience (RNN) for more than 20 years attest, clinically useful improvement can be achieved after damage or diseases of the brain, the retina, and the peripheral nervous system. By reviewing both pre-clinical studies and clinical work, we explore what advancements can be made today and what to expect going forward. For example, in the last few years we have seen a clinical focus in the area of non-invasive brain stimulations and rehabilitation training trials. In basic animal research multi-modal approaches have been presented to restore brain function with a combination of different treatments. We think that this is an exciting time in the area of restoration of brain function with many new strategies aimed at helping recovering their impaired neurological functions.

The translational imperative: Making cell therapy simple and effective

The current practice of cell therapy, in which multipotent or terminally differentiated cells are injected into tissues or intravenously, is inefficient. Few therapeutic cells are retained at the site of administration and engraftment is low. An injectable and biologically appropriate vehicle for delivery, retention, growth and differentiation of therapeutic cells is needed to improve the efficacy of cell therapy. We focus on a hyaluronan-based semi-synthetic extracellular matrix (sECM), HyStem®, which is a manufacturable, approvable and affordable clinical product. The composition of this sECM can be customized for use with mesenchymal stem cells as well as cells derived from embryonic or induced pluripotent sources. In addition, it can support therapeutic uses of progenitor and mature cell populations obtained from skin, fat, liver, heart, muscle, bone, cartilage, nerves and other tissues. This overview presents four pre-clinical uses of HyStem® for cell therapy to repair injured vocal folds, improve post-myocardial infarct heart function, regenerate damaged liver tissue and restore brain function following ischemic stroke. Finally, we address the real-world limitations – manufacture, regulation, market acceptance and financing – surrounding cell therapy and the development of clinical combination products.

Human umbilical cord blood mesenchymal stem cells protect mice brain after trauma*

To investigate whether human umbilical cord blood mesenchymal stem cells, a novel source of progenitors with multilineage potential: 1) decrease traumatic brain injury sequelae and restore brain function; 2) are able to survive and home to the lesioned region; and 3) induce relevant changes in the environment in which they are infused. Prospective experimental study. Research laboratory. Male C57Bl/6 mice. Mice were subjected to controlled cortical impact/sham brain injury. At 24 hrs postinjury, human umbilical cord blood mesenchymal stem cells (150,000/5 μL) or phosphate-buffered saline (control group) were infused intracerebroventricularly contralateral to the injured side. Immunosuppression was achieved by cyclosporine A (10 mg/kg intraperitoneally). After controlled cortical impact, human umbilical cord blood mesenchymal stem cell transplantation induced an early and long-lasting improvement in sensorimotor functions assessed by neuroscore and beam walk tests. One month postinjury, human umbilical cord blood mesenchymal stem cell mice showed attenuated learning dysfunction at the Morris water maze and reduced contusion volume compared with controls. Hoechst positive human umbilical cord blood mesenchymal stem cells homed to lesioned tissue as early as 1 wk after injury in 67% of mice and survived in the injured brain up to 5 wks. By 3 days postinjury, cell infusion significantly increased brain-derived neurotrophic factor concentration into the lesioned tissue, restoring its expression close to the levels observed in sham operated mice. By 7 days postinjury, controlled cortical impact human umbilical cord blood mesenchymal stem cell mice showed a nonphagocytic activation of microglia/macrophages as shown by a selective rise (260%) in CD11b staining (a marker of microglia/macrophage activation/recruitment) associated with a decrease (58%) in CD68 (a marker of active phagocytosis). Thirty-five days postinjury, controlled cortical impact human umbilical cord blood mesenchymal stem cell mice showed a decrease of glial fibrillary acidic protein positivity in the scar region compared with control mice. These findings indicate that human umbilical cord blood mesenchymal stem cells stimulate the injured brain and evoke trophic events, microglia/macrophage phenotypical switch, and glial scar inhibitory effects that remodel the brain and lead to significant improvement of neurologic outcome.

Deciphering the neuroprotective mechanisms of Bu-yang Huan-wu decoction by an integrative neurofunctional and genomic approach in ischemic stroke mice

Ethnopharmacological relevanceBu-yang Huan-wu decoction (BHD) is a famous traditional Chinese medicine formula that has been used clinically in Asia to treat stroke-induced disability for centuries, but the underlying neuroprotective mechanisms are not fully understood. Aim of the studyIn this study, we aim to investigate the mechanisms of action using an integrative neurofunctional and broad genomics approach. Materials and methodsMale ICR mice were subjected to an acute ischemic stroke by inducing a middle cerebral ischemic/reperfusion (CI/R) injury. To examine whether BHD could extend the lifespan of mice with a stroke, we used oral administration of BHD (0.5 and 1.0g/kg) twice daily starting from 2h after ischemia and compared this with vehicle control treatments, recombinant tissue-type plasminogen activator (rt-PA, 10mg/kg, i.v.), and MK-801 (0.2mg/kg, i.p.). An integrative neurofunctional and genomic approach was performed to elucidate the underlying molecular mechanisms of BHD. ResultsMore than 80% of the mice died within 2 days after stroke induction in the vehicle control treatment group. However, the survival rates and life-spans of mice treated with BHD, rt-PA and MK-801 were significantly enhanced as compared to the vehicle-treated CI/R group in all three cases. Mice treated with BHD (1.0g/kg) showed the greatest protective effect across all groups. BHD successfully restored brain function, ameliorated the cerebral infarction, and significantly improved the neurological deficits of the mice with a stroke. BHD also reduced inflammation, oxidative stress, and apoptosis, as well as improved neurogenesis. The molecular impacts of BHD were assessed by genome-wide transcriptome analysis using brains from the CI/R mice. The results showed a total of 377 ischemia-induced probe-sets that were significantly influenced by BHD including 93 probe-sets that were commonly more abundant in BHD-treated and sham mice, and another 284 ischemia-induced probe sets that were suppressed by BHD. Mining the functional modules and genetic networks of these 377 genes revealed a significant upregulation of neuroprotective genes associated with neurogenesis (6 genes) and nervous system development (9 genes), and a significant down-regulation of destructive genes associated with the induction of inflammation (14 genes), apoptosis (15 genes), angiogenesis (11 genes) and blood coagulation (7 genes) by BHD. ConclusionsOur results suggested that BHD is able to protect mice against stroke and extend lifespan primarily through a significant down-regulation of genes involved in inflammation, apoptosis, angiogenesis and blood coagulation, as well as an up-regulation of genes mediating neurogenesis and nervous system development. The changes in expression after treatment with BHD are beneficial after ischemic stroke.

Regulation of adult neurogenesis in the hippocampus by stress, acetylcholine and dopamine

Neurogenesis is well-established to occur during adulthood in two regions of the brain, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. Research for more than two decades has implicated a role for adult neurogenesis in several brain functions including learning and effects of antidepressants and antipsychotics. Clear understanding of the players involved in the regulation of adult neurogenesis is emerging. We review evidence for the role of stress, dopamine (DA) and acetylcholine (ACh) as regulators of neurogenesis in the SGZ. Largely, stress decreases neurogenesis, while the effects of ACh and DA depend on the type of receptors mediating their action. Increasingly, the new neurons formed in adulthood are potentially linked to crucial brain processes such as learning and memory. In brain disorders like Alzheimer and Parkinson disease, stress-induced cognitive dysfunction, depression and age-associated dementia, the necessity to restore brain functions is enormous. Activation of the resident stem cells in the adult brain to treat neuropsychiatric disorders has immense potential and understanding the mechanisms of regulation of adult neurogenesis by endogenous and exogenous factors holds the key to develop therapeutic strategies for the debilitating neurological and psychiatric disorders.

Delayed transplantation of human neural precursor cells improves outcome from focal cerebral ischemia in aged rats

Neural precursor cell (NPC) transplantation may have a role in restoring brain function after stroke, but how aging might affect the brain's receptivity to such transplants is unknown. We reported previously that transplantation of human embryonic stem cell (hESC)-derived NPCs together with biomaterial (Matrigel) scaffolding into the brains of young adult Sprague-Dawley rats 3 weeks after distal middle cerebral artery occlusion (MCAO) reduced infarct volume and improved neurobehavioral performance. In this study, we compared the effect of NPC and Matrigel transplants in young adult (3-month-old) and aged (24-month-old) Fisher 344 rats from the National Institute on Aging's aged rodent colony. Distal MCAO was induced by electrocoagulation, and hESC-derived NPCs were transplanted into the infarct cavity 3 weeks later. Aged rats developed larger infarcts, but infarct volume and performance on the cylinder and elevated body swing tests, measured 6-8 weeks post-transplant, were improved by transplantation. We conclude that advanced age does not preclude a beneficial response to NPC transplantation following experimental stroke.

A screening, prevention, and restoration model for saving the injured brain in intensive care unit survivors

We face a profound and emerging public health problem in the form of acute and chronic brain dysfunction. This affects both young and elderly intensive care unit survivors and is altering the landscape of society. Two-thirds of intensive care unit patients develop delirium, and this is associated with longer stays, increased costs, and excess mortality. In addition, over half of intensive care unit survivors suffer a dementia-like illness that impacts their physical and cognitive functional abilities and which appears to be related to the duration of their intensive care unit delirium. A new paradigm of how intensivists handle the brain is required. We propose a three-step approach to address this emerging epidemic, which includes Screening, Prevention, and Restoration of brain function (SPR). Screening combines risk factor identification and delirium assessment using validated instruments. Prevention of acute and chronic brain dysfunction requires implementation of a core model of care that combines evidence-based practices: awakening and breathing, coordination with target-based sedation, delirium monitoring, and exercise/early mobility (ABCDE). Restoration introduces strategies of ongoing screening and treatment for intensive care unit survivors at high risk of ongoing brain dysfunction. This practical system applying many evidence-based concepts incorporates personalized medicine, systems-based practice, and continuing research and development toward improving acute and chronic cognitive outcomes.

Reversal of neuronal and cognitive consequences of amphetamine sensitization following chronic treatment with a D1 antagonist

Neuroplasticity is a key factor in restoration of brain function following neuropathology associated with disease or drug exposure. Here we examined the potential for chronic treatment with the selective D1 receptor antagonist SCH39166 to reverse the profound and enduring cognitive impairment associated with amphetamine (AMPH) sensitization in the nonhuman primate and to stimulate re-growth of atrophied pyramidal dendrites in the dorsolateral prefrontal cortex of these animals. Four rhesus monkeys with sustained cognitive impairment (> 1 year following AMPH sensitization) were treated for up to 8 months with SCH39166. Cognitive testing was performed before, during, and for up to 1½ year following treatment. Significant improvement in working memory performance was observed only after cessation of the D1 antagonist treatment but then was sustained for the duration of the post-treatment testing period. Postmortem quantitative assessment of Golgi-impregnated pyramidal neurons in BA9 showed that apical dendritic length and trunk spine density were increased in D1 antagonist treated monkeys relative to AMPH-sensitized and AMPH-naïve monkeys. These findings, which suggest that the deleterious consequences of AMPH sensitization can be reversed by modulation of D1 receptor signaling, have implications for treating the underlying neural basis of cognitive deficits in both schizophrenia and substance abuse.

Neuromodulation

Many nervous system disorders (e.g., Parkinson's disease, mood disorders) involve neurotransmitters as well as electrical activity. Pharmacologic treatment does not target the precise location(s) where neurotransmitter imbalances occur. Additionally, non-neuronal cells in the brain--notably astrocytes--influence neuronal activity through both electrical and neurochemical modulation of nearby neurons. Precise monitoring/recording and modulating/stimulating (both electrical and neurochemical) can optimize therapy in specific disorders and specific patients. Carbon-fiber microelectrodes (5 microm diameter) in freely moving rodents have shown that dopamine release is heterogeneous within various regions in the nucleus accumbens, a region involved in many mood disorders. Because neurons are only several microns in diameter (axons, dendrites, and synaptic clefts smaller still), ultramicroelectrodes will be essential to selectively monitor/modulate the cell body, the axon, or at the intracellular level. Nanoelectrode arrays can monitor both electrical activity and dopamine in real time with submicron resolution, and stimulate neurons with equal precision. Computational models indicate that precise monitoring/modulating (electrically and neurochemically) at the subnucleus or neuron level will be necessary to restore normal firing patterns and neurotransmitter levels in many brain disorders. Endovascular techniques can introduce ultramicroelectrodes (0.5 micron or smaller) into the brain via capillaries; such electrodes can stimulate/record neuronal tissue with a response virtually identical to extra-vascular microelectrodes. Within the next decade, hundreds if not thousands of submicron-sized monitoring/modulating electrodes can be placed wherever needed to restore brain function to normal. The term "neuromodulation" will likely replace deep brain stimulation (DBS) as both neurochemistry and electrical activity are included in the therapeutic modalities.

EEG Measures Index Neural and Cognitive Recovery from Sleep Deprivation

Sleep deprivation impairs many cognitive abilities, but these impairments can be reversed after a certain quantity and quality of sleep. The ability to inhibit responding is particularly susceptible to disruption after prolonged wakefulness. How recovery sleep (RS) alters brain activity, leading to improved performance on a variety of cognitive tasks, remains unclear. This issue was examined in the current study using spectral analysis of electroencephalogram (EEG) data during sleep. These measures of sleep physiology were acquired after both normal sleep (NS) and RS, and were related to measures of inhibitory control and concurrent brain activity. Subjects were nine young adults who underwent functional magnetic resonance imaging twice, after 9 h of NS and after 10 h of RS that followed 38 h of being awake. A multiple regression model was used to examine differences between conditions in (1) EEG spectral power during sleep, (2) probability of successful inhibition in a go/no-go task, and (3) activation within a region of right prefrontal cortex during the task. Performance recovery, as indexed by reduced performance differences between conditions, was predicted by increased delta power and decreased sigma power in RS compared with NS. These EEG variables predicted most of the variance in inhibitory performance difference between conditions. Regressions also suggested that RS improved performance because of changes in brain function including prefrontal regions that resulted from delta rebound. We thus propose that slow waves, reflected in delta power during RS, act to restore brain function, thereby improving cognitive performance that entails response inhibition.

Enriched Environment Reduces Apolipoprotein E (ApoE) in Reactive Astrocytes and Attenuates Inflammation of the Peri-Infarct Tissue after Experimental Stroke

Apolipoprotein E (ApoE), a cholesterol transporter and an immunomodulator, is brain protective after experimental stroke and implicated in brain repair. Here, we study the involvement of ApoE in the restoration of brain function after experimental stroke, by using animal housing conditions that differentially improve recovery after occlusion of the middle cerebral artery occlusion (MCAO). We found that after MCAO the ApoE levels increased in the injured hemisphere over a 30 days recovery period. The exception was a proximal narrow peri-infarct rim, in which ApoE was solely localized in S100beta(+)/glial fibrillary acidic protein (GFAP) negative reactive astrocytes at 4 to 7 days of recovery. Enriched housing after MCAO caused a marked decrease in ApoE levels compared with standard housing conditions, particularly in the ApoE/S100beta(+) reactive astrocytes. In addition, the levels of interleukin 1beta were lower in animals housed in an enriched environment. We propose that during the subacute phase after experimental stroke a zone for tissue reorganization with low cellular ApoE levels is formed. We conclude that the strong sensori-motor stimulation provided by enriched housing conditions mitigates the inflammatory response after stroke decreasing the level of ApoE that may contribute to the observed improvement of functional recovery.

Neurosphere-Derived Cells Exert a Neuroprotective Action by Changing the Ischemic Microenvironment

BackgroundNeurosphere-derived cells (NC), containing neural stem cells, various progenitors and more differentiated cells, were obtained from newborn C57/BL6 mice and infused in a murine model of focal ischemia with reperfusion to investigate if: 1) they decreased ischemic injury and restored brain function; 2) they induced changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia were relevant for NC action.Methodology/Principal FindingsNC were infused intracerebroventricularly 4 h or 7 d after 30 min middle cerebral artery occlusion. In ischemic mice receiving cells at 4 h, impairment of open field performance was significantly improved and neuronal loss significantly reduced 7–14 d after ischemia compared to controls and to ischemic mice receiving cells at 7 d. Infusion of murine foetal fibroblast in the same experimental conditions was not effective. Assessment of infused cell distribution revealed that they migrated from the ventricle to the parenchyma, progressively decreased in number but they were observable up to 14 d. In mice receiving NC at 7 d and in sham-operated mice, few cells could be observed only at 24 h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as Insulin Growth Factor-1, Vascular Endothelial Growth Factor-A, Transforming Growth Factor-β1, Brain Derived Neurotrophic Factor and Stromal Derived Factor−1α, as well as microglia/macrophage activation, increased 24 h after NC infusion in ischemic mice treated at 4 h compared to sham-operated and to mice receiving cells at 7 d.Conclusions/SignificanceNC reduce functional impairment and neuronal damage after ischemia/reperfusion injury. Several lines of evidence indicate that the reciprocal interaction between NC and the ischemic environment is crucial for NC protective actions. Based on these results we propose that a bystander control of the ischemic environment may be the mechanism used by NC to rapidly restore acutely injured brain function.

Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP‐activated protein kinase

Hepatic encephalopathy (HE) is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We studied the etiology of cerebral dysfunction in a murine model of HE induced by either bile duct ligation or thioacetamide administration. We report that stimulation of cerebral AMP-activated protein kinase (AMPK), a major intracellular energy sensor, is a compensatory response to liver failure. This function of AMPK is regulated by endocannabinoids. The cannabinoid system controls systemic energy balance via the cannabinoid receptors CB-1 and CB-2. Under normal circumstances, AMPK activity is mediated by CB-1 while CB-2 is barely detected. However, CB-2 is strongly stimulated in response to liver failure. Administration of delta9-tetrahydrocannabinol (THC) augmented AMPK activity and restored brain function in WT mice but not in their CB-2 KO littermates. These results suggest that HE is a disease of energy flux. CB-2 signaling is a cerebral stress response mechanism and makes AMPK a promising target for its treatment by modulating the cannabinoid system.

Iron, Oxidative Stress and Early Neurological Deterioration in Ischemic Stroke

Ischemic stroke is characterized by the disruption of cerebral blood flow, which produces a central core of dead neurons surrounded by a penumbra of damaged but partially functional neurons. Many factors are associated with such brain injury, including excitotoxicity and free radicals. Recent clinical studies have shown that high plasma ferritin levels are detrimental in acute ischemic stroke. As an iron-storage protein, ferritin can act both as a scavenger and as a donor of free iron, which is a source of hydroxyl radicals. Following disruption of the blood-brain barrier, the ferritin and the free iron that have accumulated in endothelial cells in brain capillaries, together with plasma ferritin, can enter the penumbra. Iron-dependent oxidative stress in the penumbra can lead to necrosis and further neurological deterioration following ischemic stroke. An excess of iron should be considered pathological in the ischemic brain. Therapeutic strategies for ischemic stroke should attempt to restore brain function within the penumbra. Consequently, the iron content of systemic stores should be measured, and anti-oxidant treatment should be considered when it is excessive.

Therapeutic Potential of Adult Neural Stem Cells

The central nervous system (CNS) elicits limited capacity to recover from injury. Though considerable efforts and means have been deployed to find treatments for neurological diseases, disorders and injuries, there is still no cure for these ailments, and new alternatives for therapy must be explored. Because they generate the main phenotypes of the nervous system, neural stem cells (NSCs) hold the promise to cure a broad range of neurological diseases and injuries. With the confirmation that neurogenesis occurs in the adult brain and NSCs reside in the adult CNS, new treatments for neurological diseases and injuries are being considered. Particularly, the transplantation of adult-derived neural progenitor and stem cells to restore brain functions. In this manuscript, we will review the recent developments in adult neurogenesis and NSCs, and patent applications filed in relation to discoveries made in this new field of research.

The Impact of Motor Activity and Inactivity on the Brain

Since Donald Hebb's pioneering observations in the 1940s, much research has focused on the effects of variations in physical activity and environmental complexity on behavioral performance and brain structure. Beneficial effects on brain health have been linked to physical fitness, skilled training, and exposure to complex environments, though in rodents these effects may be negated by sudden changes in social structure. Such manipulations can alleviate the deficits associated with several nervous-system disorders and aging. But how increased activity produces its beneficial effects is still not fully understood. How does unskilled physical activity (e.g., repetitive exercise) compare to training in skilled activities or exposure to complex environments? In injury states, is task-specific training a better rehabilitative strategy than general exercise? How do changes in motor activity affect specific brain regions, and can the intensity and timing of therapeutic movement be adjusted to produce optimal outcomes? Are the beneficial effects of motor enrichment banked over periods of inactivity and can they be called upon with booster training to treat a later neurological disorder? Are there circumstances in which increased activity is harmful? Enrichment of physical activity shows promise as an easy and healthful means for improving or restoring brain function, and questions like these are now being investigated so that the full potential of increased activity may be harnessed.