Recovery Of Brain Function Research Articles

Abstract 122: The Role of Plasma Lysophosphatidylcholine in Patients With Out-of-Hospital Cardiac Arrest

Background: Phosphatidylcholine (PC) is the most abundant class of phospholipid found in plasma. Lysophosphatidylcholine (LPC), PC missing one acyl chain, is believed to be the main carrier of polyunsaturated fatty acids (PUFAs) to the brain. The continuous supply of PUFAs, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA), are important to maintain proper function of the brain. Therefore, alterations in the plasma levels of LPC containing these fatty acids, LPC-EPA, LPC-DHA, and LPC-AA, indicate impaired delivery of fatty acids, which in turn may indicate abnormal brain function. Numerous animal studies have found altered LPC compositions in Alzheimer’s disease, cognitive impairment, brain ischemia, and aging. Moreover, administration of LPC has been shown to improve brain function in these pathological conditions. Since brain damage is the main cause of death in cardiac arrest, altered LPC profiles may be indicative of brain damage and also play a role in the recovery of brain function. The aim of this study was to measure the content of plasma LPC species in out-of-hospital cardiac arrest (OHCA) patients compared to healthy controls. Methods: Blood samples were obtained from 11 OHCA patients, who were admitted to Northshore University Hospital and achieved return of spontaneous circulation. Within 4 h of drawing, plasma was separated from the whole blood using centrifugation and stored at -80°C. Control samples were obtained from 19 healthy volunteers. The contents of LPC species were measured using LC-mass spectrometry. Results: We found the overall content of LPC is significantly lower in OHCA patients. The decrease is found in all species of LPC, including LPC-EPA (patients vs Controls = 0.17 vs 0.55 μmol/L, p=0.003), LPC-DHA (patients vs Controls = 0.47 vs 1.72 μmol/L, p=0.003), and LPC-AA (patients vs Controls = 1.98 vs 5.39 μmol/L, p<0.001). We also found decreased in LPC species containing saturated fatty acids, showing the decrease was not specific to PUFAs. Conclusion: We found OHCA patients have a significantly lower plasma LPC content. Understanding the detailed mechanism for this decrease and the role that LPC plays in the recovery of patients after OHCA requires more investigation.

Pentraxin 3 promotes long-term cerebral blood flow recovery, angiogenesis, and neuronal survival after stroke

Restoration of cerebral blood flow (CBF) and upregulation of angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia. Pentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke. Here, we investigated for the first time the role of PTX3 in long-term CBF, angiogenesis, and neuronal viability after ischaemic stroke induced by transient middle cerebral artery occlusion (MCAo). Lack of PTX3 had no effect on early brain damage, but significantly impaired restoration of CBF, 14 and 28 days after MCAo, compared to wild-type (WT) mice. Immunohistochemical analysis revealed that PTX3 KO mice have significantly greater neuronal loss, significantly decreased vessel diameter, vessel proliferation, vascular density, and reactive astrocytes and decreased expression of vascular endothelial growth factor receptor 2 (VEGR2), vascular extracellular matrix (ECM)-proteins (collagen IV, laminin), and integrin-β, in the ipsilateral (stroke) hemisphere compared to WT mice, 28 days after MCAo. Therefore, PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia. Collectively, these findings demonstrate the potential and clinical relevance of PTX3 as a promising therapeutic target, providing sustained long-term post-stroke neurovascular repair and reducing the loss of neurons.Key messagesPentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke.Restoration of cerebral blood flow (CBF) and angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia.PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia.

Neuroprotective Effects of DTIO, A Novel Analog of Nec-1, in Acute and Chronic Stages After Ischemic Stroke

Receptor-interacting protein 1 kinase (RIP1K) plays a key role in necroptosis. Necrostatin-1 (Nec-1), a specific inhibitor of RIP1K, provides neuroprotection against ischemic brain injury, associating with inhibition of inflammation. Recently, our group synthesized a novel analog of Nec-1, 5-(3′,5′-dimethoxybenzal)-2-thio-imidazole-4-ketone (DTIO). The present study investigated the effect of DTIO on ischemic stroke-induced brain injury in both acute and chronic phase and its underlying mechanism. In vivo, DTIO treatment reduced infarct volume and improved neurological deficits in the acute phase after permanent middle cerebral artery occlusion (pMCAO) and it also attenuated brain atrophy and promoted brain functional recovery in the chronic phase post-cerebral ischemia/reperfusion (I/R). In vitro, DTIO treatment decreased lactate dehydrogenase (LDH) leakage and necrotic cell death in the oxygen and glucose deprivation (OGD) or oxygen and glucose deprivation and reoxygenation (OGD/R)-induced neuronal or astrocytic cell injury. Simultaneously, DTIO suppressed the production and release of inflammatory cytokines, and reduced the formation of glial scar. Homology modeling analysis illustrated that DTIO had an ability of binding to RIP1K. Furthermore, immunoprecipitation analysis showed that DTIO inhibited the phosphorylation of RIP1K and decreased the interaction between the RIP1K and RIP3K. In addition, knockdown of RIP1K had neuroprotective effects and inhibited the release of proinflammatory cytokines, but didn’t have a significant effect on DTIO-mediated neuroprotection. In conclusion, DTIO has protective effects on acute ischemic stroke and promotes functional recovery during chronic phase, associating with protecting ischemic neurons and astrocytes, inhibiting inflammation, and lessening the glial scar formation via inhibiting of the RIP1K.

Ghrelin Ameliorates Traumatic Brain Injury by Down-Regulating bFGF and FGF-BP.

Traumatic brain injury (TBI) is a primary cause of disability and mortality. Ghrelin, a gastrointestinal hormone, has been found to have protective effects for the brain, but the molecular mechanism of these neuroprotective effects of ghrelin remains unclear. In this study, an electronic cortical contusion impactor was used to establish a rat TBI model and we investigated the effect of ghrelin on brain repair by neurological severity score and histological examination. An antibody array was employed to uncover the molecular mechanism of ghrelin’s neuroprotective effects by determining the alterations of multiple proteins in the brain cortex. As a result, ghrelin attenuated brain injury and promoted brain functional recovery. After TBI, 13 proteins were up-regulated in the brain cortex, while basic fibroblast growth factor (bFGF) and fibroblast growth factor-binding protein (FGF-BP) were down-regulated after ghrelin treatment. It is known that bFGF can induce angiogenesis in the brain and accelerate wound healing, which can be further enhanced by FGF-BP. Based on the previous studies, it is hypothesized that the exogenous ghrelin curing TBI might cause the closure of bFGF and FGF-BP functions on wound healing, or ghrelin might exert the neuroprotective effects by competitively inhibiting bFGF/FGF-BP-induced neovascularization. Whether the combinational administration of ghrelin and bFGF/FGF-BP can enhance or weaken the therapeutic effect on TBI requires further research.

Biomaterials driving repair after stroke.

An injectable biomaterial with angiogenic and immune-modulatory properties was developed and shown to support brain tissue repair and functional recovery in a mouse model of stroke.

Sema3E/PlexinD1 inhibition is a therapeutic strategy for improving cerebral perfusion and restoring functional loss after stroke in agedrats.

Brain tissue survival and functional recovery after ischemic stroke greatly depend on cerebral vessel perfusion and functional collateral circulation in the ischemic area. Semaphorin 3E (Sema3E), one of the class 3 secreted semaphorins, has been demonstrated to be a critical regulator in embryonic and postnatal vascular formation via binding to its receptor PlexinD1. However, whether Sema3E/PlexinD1 signaling is involved in poststroke neovascularization remains unknown. To determine the contribution of Sema3E/PlexinD1 signaling to poststroke recovery, aged rats (18months) were subjected to a transient middle cerebral artery occlusion. We found that depletion of Sema3E/PlexinD1 signaling with lentivirus-mediated PlexinD1-specific-shRNA improves tissue survival and functional outcome. Sema3E/PlexinD1 inhibition not only increases cortical perfusion but also ameliorates blood-brain barrier damage, as determined by positron emission tomography and magnetic resonance imaging. Mechanistically, we demonstrated that Sema3E suppresses endothelial cell proliferation and angiogenic capacity. More importantly, Sema3E/PlexinD1 signaling inhibits recruitment of pericytes by decreasing production of platelet derived growth factor-BB in endothelial cells. Overall, our study revealed that inhibition of Sema3E/PlexinD1 signaling in the ischemic penumbra, which increases both endothelial angiogenic capacity and recruitment of pericytes, contributed to functional neovascularization and blood-brain barrier integrity in the aged rats. Our findings imply that Sema3E/PlexinD1 signaling is a novel therapeutic target for improving brain tissue survival and functional recovery after ischemic stroke.

Interstitial ion homeostasis and acid-base balance are maintained in oedematous brain of mice with acute toxic liver failure

Acute toxic liver failure (ATLF) rapidly leads to brain oedema and neurological decline. We evaluated the ability of ATLF-affected brain to control the ionic composition and acid-base balance of the interstitial fluid. ATLF was induced in 10–12 weeks old male C57Bl mice by single intraperitoneal (i.p.) injection of 100 μg/g azoxymethane (AOM). Analyses were carried out in cerebral cortex of precomatous mice 20–24 h after AOM administration. Brain fluid status was evaluated by measuring apparent diffusion coefficient [ADC] using NMR spectroscopy, Evans Blue extravasation, and accumulation of an intracisternally-injected fluorescent tracer. Extracellular pH ([pH]e) and ([K+]e) were measured in situ with ion-sensitive microelectrodes. Cerebral cortical microdialysates were subjected to photometric analysis of extracellular potassium ([K+]e), sodium ([Na+]e) and luminometric assay of extracellular lactate ([Lac]e). Potassium transport in cerebral cortical slices was measured ex vivo as 86Rb uptake. Cerebral cortex of AOM-treated mice presented decreased ADC supporting the view that ATLF-induced brain oedema is primarily cytotoxic in nature. In addition, increased Evans blue extravasation indicated blood brain barrier leakage, and increased fluorescent tracer accumulation suggested impaired interstitial fluid passage. However, [K+]e, [Na+]e, [Lac]e, [pH]e and potassium transport in brain of AOM-treated mice was not different from control mice. We conclude that in spite of cytotoxic oedema and deregulated interstitial fluid passage, brain of mice with ATLF retains the ability to maintain interstitial ion homeostasis and acid-base balance. Tentatively, uncompromised brain ion homeostasis and acid-base balance may contribute to the relatively frequent brain function recovery and spontaneous survival rate in human patients with ATLF.

S24. The combination of electroencephalogram (EEG) and somatosensory evoked potentials (SSEP) for prognostication following anoxic brain injury – A pilot study from an Academic Hospital in Ireland

Introduction Clinical evaluation for prognosis of comatose patients following hypoxic ischaemic encephalopathy in the intensive care setting is difficult. Electroencephalogram (EEG) and somatosensory evoked potentials (SSEP) both hold value as predictive tools when assessing outcome following cardiac arrest (CA) and hypoxic brain injury. EEG may be used for diagnosis and prognostication on a poorly responsive patient following catastrophic brain injury. There is evidence that loss of EEG reactivity is a strong risk factor for mortality or poor neurological recovery following cardiac arrest, however, bilaterally absent SSEPs remain the most reliable predictor of poor outcome. SSEPs have not been widely available in Ireland as a component of neurophysiologic investigation following hypoxic ischaemic encephalopathy. The aim of this review is to assess and compare the predictive value of EEG and SSEP separately as single modality testing and then subsequently combine both tests for a multimodal approach to predict poor outcome following anoxic brain injury. Is a multimodal approach mandatory? Methods Seventeen cardiac arrest survivors were included in this review. We adopted a multimodal approach to neurophysiologic investigations in the ICU setting with prospective evaluation of patients of hypoxic ischaemic encephalopathy after CA. EEG and SSEPs were performed at normothermia. EEG background reactivity to painful stimulation was tested. Results Of the 17 patients included in the review, two survived to discharge and 15 subsequently died during hospitalisation. EEG was utilised as a marker for poor outcome combining malignant EEG patterns and absent reactivity of background rhythms. 11 out of 17 fitted into the “poor outcome” category for EEG, all of whom died. Bilateral absent N20 cortical responses were utilised for poor outcome, 9 out of 17 fitted into the “poor outcome” category, all of whom went on to die. However, there were eight patients included showing present N20s, this is not prognostic of a favourable outcome. A combination of EEG and SSEP was needed to predict outcome. The EEG showed malignant EEG patterns and unreactive background in 2 of the present N20 patients who subsequently went on to die. Conclusion The EEG represents a useful tool for prognostic assessment. Unreactive EEG background and malignant EEG patterns are incompatible with good long term recovery. In settings without access to SSEPs this can be helpful, however, a bilaterally absent somatosensory evoked potential is still the most reliable predictor for poor outcome. Throughout our review a multimodal approach is shown to be favourable when assessing Hypoxic Ischemic Encephalopathy. This approach, as described above, was necessary to predict outcome in cases where the N20 cortical response was present, thus optimising prognostic accuracy when assessing hypoxic brain injury in the ICU. Early identification of patients without the potential for recovery of brain function may result in unnecessary prolongation of medical therapy.

Changes in the hippocampal and peripheral phospholipid profiles are associated with neurodegeneration hallmarks in a long-term global cerebral ischemia model: Attenuation by Linalool

Phospholipid alterations in the brain are associated with progressive neurodegeneration and cognitive impairment after acute and chronic injuries. Various types of treatments have been evaluated for their abilities to block the progression of the impairment, but effective treatments targeting long-term post-stroke alterations are not available. In this study, we analyzed changes in the central and peripheral phospholipid profiles in ischemic rats and determined whether a protective monoterpene, Linalool, could modify them. We used an in vitro model of glutamate (125 μM) excitotoxicity and an in vivo global ischemia model in Wistar rats. Linalool (0.1 μM) protected neurons and astrocytes by reducing LDH release and restoring ATP levels. Linalool was administered orally at a dose of 25 mg/kg every 24 h for a month, behavioral tests were performed, and a lipidomic analysis was conducted using mass spectrometry. Animals treated with Linalool displayed faster neurological recovery than untreated ischemic animals, accompanied by better motor and cognitive performances. These results were confirmed by the significant reduction in astrogliosis, microgliosis and COX-2 marker, involving a decrease of 24:0 free fatty acid in the hippocampus. The altered profiles of phospholipids composed of mono and polyunsaturated fatty acids (PC 36:1; 42:1 (24:0/18:1)/LPC 22:6)/LPE 22:6) in the ischemic hippocampus and the upregulation of PI 36:2 and other LCFA (long chain fatty acids) in the serum of ischemic rats were prevented by the monoterpene. Based on these data, alterations in the central and peripheral phospholipid profiles after long-term was attenuated by oral Linalool, promoting a phospholipid homeostasis, related to the recovery of brain function.

Recovery of Neurovascular Unit Integrity by CDK5-KD Astrocyte Transplantation in a Global Cerebral Ischemia Model.

Astrocytes play metabolic and structural support roles and contribute to the integrity of the blood-brain barrier (BBB), linking communication between neurons and the endothelium. Cyclin-dependent kinase 5 (CDK5) likely exerts a dual effect on the endothelium and astrocytes due to its involvement in migration and angiogenesis; the overactivation of CDK5 is associated with dysfunction in glutamate recapture and hypoxia. Recently, we proposed that CDK5-targeted astrocytes facilitate the recovery of neurological and motor function in transplanted ischemic rats. In the current study, we treated cerebral ischemic rats and endothelial cells exposed to glutamate toxicity with CDK5 knock-down (CDK5-KD) astrocytes to determine the role of CDK5 in neurovascular integrity. We found that the effects of CDK5-KD were sustained for 4months, preventing neuronal and astrocyte loss, facilitating the recovery of the BBB via the production of BDNF by endogenous astrocytes (GFP-) surrounding vessels in the motor cortex and the corpus callosum of global ischemic rats, and improving neurological performance. These findings were supported by the in vitro findings of increased transendothelial resistance, p120-ctn+ adhesion and reduced intercellular gaps induced by a CDK5 inhibitor (roscovitine) in bEnd.3 cells in a glutamate-toxicity model. Additionally, CDK5-KD astrocytes in co-culture protected the endothelial cell viability, increased BDNF release from astrocytes, increased BDNF immunoreactivity in neighboring astrocytes and endothelial cells and enhanced cell adhesion in a glutamate-toxicity model. Altogether, these findings suggest that a CDK5 reduction in astrocytes protects the endothelium, which promotes BDNF release, endothelial adhesion, and the recovery of neurovascular unit integrity and brain function in ischemic rats.

Ras-Related C3 Botulinum Toxin Substrate 1 Promotes Axonal Regeneration after Stroke in Mice.

Neurite plasticity is a critical aspect of brain functional recovery after stroke. Emerging data suggest that Ras-related C3 botulinum toxin substrate 1 (Rac1) plays a central role in axonal regeneration in the injured brain, specifically by stimulating neuronal intrinsic growth and counteracting the growth inhibitory signaling that leads to growth cone collapse. Therefore, we investigated the functional role of Rac1 in axonal regeneration after stroke.Delayed treatment with a specific Rac1 inhibitor, NSC 23766, worsened functional recovery, which was assessed by the pellet reaching test from day14 to day28 after stroke. It additionally reduced axonal density in the peri-infarct zone, assessed 28days after stroke, with no effect on brain cavity size or on the number of newly formed cells. Accordingly, Rac1 overexpression using lentivirus promoted axonal regeneration and functional recovery after stroke from day14 to day28. Rac1 inhibition led to inactivation of pro-regenerative molecules, including mitogen-activated protein kinase kinase (p-MEK)1/2, LIM domain kinase (LIMK)1, and extracellular signal-regulated kinase (p-ERK)1/2 at 14days after stroke. Inhibition of Rac1 reduced axonal length and number in cultured primary mouse cortical neurons using microfluidic chambers after oxygen-glucose deprivation (OGD) without affecting cell viability. In contrast, inhibition of Rac1 increased levels of glial fibrillary acidic protein, an extrinsic inhibitory signal for axonal growth, after stroke in vivo and in primary astrocytes after OGD.In conclusion, Rac1 signaling enhances axonal regeneration and improve post-stroke functional recovery in experimental models of stroke.

A case with Pallister-Killian syndrome misdiagnosed as mucopolysaccharidosis

Receptor-interacting protein 1 kinase (RIP1K) plays a key role in necroptosis. Necrostatin-1 (Nec-1), a specific inhibitor of RIP1K, provides neuroprotection against ischemic brain injury, associating with inhibition of inflammation. Recently, our group synthesized a novel analog of Nec-1, 5-(3′,5′-dimethoxybenzal)-2-thio-imidazole-4-ketone (DTIO). The present study investigated the effect of DTIO on ischemic stroke-induced brain injury in both acute and chronic phase and its underlying mechanism. In vivo, DTIO treatment reduced infarct volume and improved neurological deficits in the acute phase after permanent middle cerebral artery occlusion (pMCAO) and it also attenuated brain atrophy and promoted brain functional recovery in the chronic phase post-cerebral ischemia/reperfusion (I/R). In vitro, DTIO treatment decreased lactate dehydrogenase (LDH) leakage and necrotic cell death in the oxygen and glucose deprivation (OGD) or oxygen and glucose deprivation and reoxygenation (OGD/R)-induced neuronal or astrocytic cell injury. Simultaneously, DTIO suppressed the production and release of inflammatory cytokines, and reduced the formation of glial scar. Homology modeling analysis illustrated that DTIO had an ability of binding to RIP1K. Furthermore, immunoprecipitation analysis showed that DTIO inhibited the phosphorylation of RIP1K and decreased the interaction between the RIP1K and RIP3K. In addition, knockdown of RIP1K had neuroprotective effects and inhibited the release of proinflammatory cytokines, but didn’t have a significant effect on DTIO-mediated neuroprotection. In conclusion, DTIO has protective effects on acute ischemic stroke and promotes functional recovery during chronic phase, associating with protecting ischemic neurons and astrocytes, inhibiting inflammation, and lessening the glial scar formation via inhibiting of the RIP1K.

What Do Experimental Models Teach Us About Comorbidities in Stroke?

There is a general consensus that animal models do not perfectly represent human conditions. This is not derived from any specific event, such as an ischemic episode, but rather reflects inherent differences in the physiology, anatomy, and metabolism among different species. Disparities among species also arise from differences in assessing functional recovery in stroke. Humans place a priority in regaining function in speech, cognition, and limb control, but these functions are not always readily translatable in animal models. Moreover, because functional recovery depends on the stroke type and location, induction of an ischemic lesion in a predefined area of an animal model, at best, reflects only a subtype of human stroke. Nevertheless, certain clinical pathophysiology features of stroke, such as acute outcomes and inflammatory/immune responses, are shared in animal models.1 Combined with complementary knowledge from in vitro studies, animal models can provide valuable insight into stroke pathology at a systems level. Analyses of translational inefficiencies in stroke model systems have led to the identification of underlying issues, which include, but are not limited to, rigor in experimental design, internal and external validity, negative bias, and insufficient statistical power. Together, these inefficiencies have steered collaborative international efforts in preclinical research to overcome these challenges.2 An additional issue of importance is the insufficient understanding of stroke pathophysiology beyond the acute phase and the primary reliance on infarct volume in reporting acute outcomes. Together with a lack of inclusion of comorbidities in animal models of stroke, the development of clinical protocols based on findings from normal metabolic animals may contribute to translational failures. In light of a recent concerted effort to address the future of translational stroke research,3 this review focuses on underlying translational issues and discusses insights gained from stroke models inclusive of comorbidities in the preclinical literature. ### Stroke Pathology: A Moving Target With Multiple Components Despite …

The Potential of Stem Cells in Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a global public health concern, with limited treatment options available. Despite improving survival rate after TBI, treatment is lacking for brain functional recovery and structural repair in clinic. Recent studies have suggested that the mature brain harbors neural stem cells which have regenerative capacity following brain insults. Much progress has been made in preclinical TBI model studies in understanding the behaviors, functions, and regulatory mechanisms of neural stem cells in the injured brain. Different strategies targeting these cell population have been assessed in TBI models. In parallel, cell transplantation strategy using a wide range of stem cells has been explored for TBI treatment in pre-clinical studies and some in clinical trials. This review summarized strategies which have been explored to enhance endogenous neural stem cell-mediated regeneration and recent development in cell transplantation studies for post-TBI brain repair. Thus far, neural regeneration through neural stem cells either by modulating endogenous neural stem cells or by stem cell transplantation has attracted much attention. It is highly speculated that targeting neural stem cells could be a potential strategy to repair and regenerate the injured brain. Neuroprotection and neuroregeneration are major aspects for TBI therapeutic development. With technique advancement, it is hoped that stem cell-based therapy targeting neuroregeneration will be able to translate to clinic in not so far future.

Transcranial electrical stimulation

Transcranial electrical stimulation (tES) is a neuromodulatory technique in which low voltage constant or alternating currents are applied to the human brain via scalp electrodes. The basic idea of tES is that the application of weak currents can interact with neural processing, modify plasticity and entrain brain networks, and that this in turn can modify behaviour. The technique is now widely employed in basic and translational research, and increasingly is also used privately in sport, the military and recreation. The proposed capacity to augment recovery of brain function, by promoting learning and facilitating plasticity, has motivated a burgeoning number of clinical trials in a wide range of disorders of the nervous system.

Impact of previous episodes of hepatic encephalopathy on short-term brain function recovery after liver transplantation: a functional connectivity strength study.

Neuropsychological studies have documented an incomplete reversal of pre-existing cognitive dysfunction in cirrhotic patients after liver transplantation (LT) and have found this is more severe in patients with hepatic encephalopathy (HE). In this study, we aimed to investigate the impact of prior HE episodes on post-transplantation brain function recovery. Resting-state functional magnetic resonance imaging data was collected from 30 healthy controls and 33 cirrhotic patients (HE, n = 15 and noHE, n = 18) before and one month after LT. Long- and short-range functional connectivity strength (FCS) analysis indicated that before transplantation both noHE and HE groups showed diffuse FCS abnormalities relative to healthy controls. For the noHE group, the abnormal FCS found before LT largely returned to normal levels after LT, except for in the cerebellum, precuneus, and orbital middle frontal gyrus. However, the abnormal FCS prior to LT was largely preserved in the HE group, including high-level cognition-related (frontal and parietal lobes) and vision-related areas (occipital lobe, cuneus, and precuneus). In addition, comparisons between HE and noHE groups revealed that weaker FCS in default mode network (DMN) in HE group persisted from pre- to post- LT. Correlation analysis showed that changes in FCS in the left postcentral and right middle frontal gyrus correlated with alterations in neuropsychological performance and ammonia levels. In conclusion, the findings in this study demonstrate potential adverse effects of pre-LT episode of HE on post-LT brain function recovery, and reveal that DMN may be the most affected brain region by HE episodes, which can't be reversed by LT.

Neurotrophic and Neuroregenerative Effects of GH/IGF1.

Introduction. Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects. Methods. In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: “GH/IGF-1” associated with “neuroregeneration”, “amyotrophic lateral sclerosis”, “Alzheimer disease”, “Parkinson’s disease”, “brain”, and “neuron”. Results. Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results. Conclusions. Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone.

Effects of over-expression of SOD2 in bone marrow-derived mesenchymal stem cells on traumatic brain injury

Intravenous administration of bone marrow-derived mesenchymal stem cells (BM-MSCs) has been shown to promote nerve cell regeneration following traumatic brain injury (TBI). As the anti-oxidant defense systems in neuronal tissue including superoxide dismutase 2 (SOD2) are crucial to defend cell against oxidative stress. We proposed a new stratege to increase the therapeutic effect of MSCs by preventing cells death from oxidative stress. We overexpressed SOD2 in BM-MSCs, transplanted these MSCs into TBI model mice, assessed the protective effect of SOD2 against oxidation-induced apoptosis in BM-MSCs both in vitro and in vivo, evaluated brain functional recovery by the rotarod behavioral test, and tested the oxidation status of TBI mice brain after BM-MSCs transplantation by monitoring the superoxide dismutase, glutathione and malonaldehyde level. We found over-expression of SOD2 protected BM-MSCs from H2O2-induced cell apoptosis. Injection of SOD2 over-expressed BM-MSCs attenuated neuro-inflammation in the ipsilateral cortex of TBI mice, and protected TBI mice against loss of blood-brain barrier integrity. Furthermore, the rotarod behavioral test showed functional recovery of TBI mice after MSC treatment. Our experiments indicated that SOD2-over-expressed BM-MSCs have an improved therapeutic effect on brain injury treatment in TBI mice.

Effects of ginsenoside‑Rg1 on the proliferation and glial‑like directed differentiation of embryonic rat cortical neural stem cells invitro.

Ginsenoside-Rg1, the main active component of Panax notoginseng, exhibits a number of pharmacological functions, including promoting protein synthesis in the brain, increasing the number of synapses, improving memory and promoting recovery of brain function following injury. The effect of ginsenoside-Rg1 on proliferation and glial-like-directed differentiation in the cortical neural stem cells (NSCs) of embryonic rat brain was investigated. The present study used MTS assays to identify the optimum dose and window time of ginsenoside-Rg1 administration to stimulate the proliferation of cortical NSCs in the rat embryonic tissue. The oxygen glucose deprivation (OGD) set-up was used as a cell injury model. Immunofluorescent staining was used for identification of NSCs and subsequent observation of their proliferation and glial-like directed differentiation. Nestin expression was the marker for the presence of NSCs among the cortical cells of embryonic rat brain. The optimum dose of ginsenoside-Rg1 for proliferation of NSCs was 0.32 µg/ml. The optimum window time of 0.32 µg/ml ginsenoside-Rg1 administration on proliferation of NSCs was 6 h. Ginsenoside-Rg1 at 0.32 µg/ml concentration promoted incorporation of bromo-2-deoxyuridine, and expression of nestin and vimentin in primary and passaged NSCs, and NSCs following OGD. Ginsenoside-Rg1 had a role in promoting proliferation and glial-like-directed differentiation of cortical NSCs. The plausible explanation for these responses is that ginsenoside-Rg1 acts similarly to the growth factors to promote the proliferation and differentiation of NSCs.

P 65 Navigated repetitive transcranial magnetic stimulation – therapeutic use in early rehabilitation treatment after stroke

MRI navigated repetitive transcranial magnetic stimulation (nTMS) provides a new tool for neuromodulation – we report on its effects on recovery of brain function in a setting of inpatient rehabilitation early after stroke. MRI based nTMS (inhibitory stimulus paradigm, 900 pulses at an intensity of 110% motor threshold, applied at 1 Hz) oft the contralesional primary motor cortex. Each patient participated in a median of 7 stimulation sessions, 3 sessions per week. Each stimulation session was followed by an immediate session of physical therapy, logopedic or ergotherapeutic treatment. A total of 27 cases were subject to at least 3 nTMS sessions (range 3–19 sessions) in addition to the standard multimodal therapeutic setting. The vast majority of cases experienced an improvement of motor deficit, neglect and dysphagia. The activities of daily life (Barthel) index increased from 15 to 30 points median. Two thirds of the patients were enabled to continue rehabilitation in phase C. Adverse events did not occur. The application of nTMS for early rehabilitation purposes in stroke patients is safe and effective. It appears to uncover a regeneration potential still hidden. Thus it may become a useful therapeutic adjunct to the standard multimodal approach.