Intermittent theta-burst stimulation alleviates hypoxia-ischemia-caused myelin damage and neurologic disability.

Neonatal hypoxia-ischemia (HI) results in behavioral deficits, characterized by neuronal injury and retarded myelin formation. To date, limited treatment methods are available to prevent or alleviate neurologic sequelae of HI. Intermittent theta-burst stimulation (iTBS), a non-invasive therapeutic procedure, is considered a promising therapeutic tool for treating some neurocognitive disorders and neuropsychiatric diseases. Hence, this study aims to investigate whether iTBS can prevent the negative behavioral manifestations of HI and explore the mechanisms for associations. We exposed postnatal day 10 Sprague-Dawley male and female rats to 2 h of hypoxia (6% O2) following right common carotid artery ligation, resulting in oligodendrocyte (OL) dysfunction, including reduced proliferation and differentiation of oligodendrocyte precursor cells (OPCs), decreased OL survival, and compromised myelin in the corpus callosum (CC) and hippocampal dentate gyrus (DG). These alterations were concomitant with cognitive dysfunction and depression-like behaviors. Crucially, early iTBS treatment (15 G, 190 s, seven days, initiated one day post-HI) significantly alleviated HI-caused myelin damage and mitigated the neurologic sequelae both in male and female rats. However, the late iTBS treatment (initiated 18 days after HI insult) could not significantly impact these behavioral deficits. In summary, our findings support that early iTBS treatment may be a promising strategy to improve HI-induced neurologic disability. The underlying mechanisms of iTBS treatment are associated with promoting the differentiation of OPCs and alleviating myelin damage.

Activation of testosterone-androgen receptor mediates cerebrovascular protection by photobiomodulation treatment in photothrombosis-induced stroke rats.

RATIONALE: Numerous epidemiological studies have reported a link between low testosterone levels and an increased risk of cerebrovascular disease in men. However, there is ongoing controversy surrounding testosterone replacement therapy due to potential side effects. PBMT has been demonstrated to improve cerebrovascular function and promote testosterone synthesis in peripheral tissues. Despite this, the molecular mechanisms that could connect PBMT with testosterone and vascular function in the brain of photothrombosis (PT)-induced stroke rats remain largely unknown. METHODS: We measured behavioral performance, cerebral blood flow (CBF), vascular permeability, and the expression of vascular-associated and apoptotic proteins in PT-induced stroke rats treated with flutamide and seven consecutive days of PBM treatment (350 mW, 808 nM, 2 min/day). To gain further insights into the mechanism of PBM on testosterone synthesis, we used testosterone synthesis inhibitors to study their effects on bEND.3 cells. RESULTS: We showed that PT stroke caused a decrease in cerebrovascular testosterone concentration, which was significantly increased by 7-day PBMT (808 nm, 350 mW/cm2 , 42 J/cm2 ). Furthermore, PBMT significantly increased cerebral blood flow (CBF) and the expression of vascular-associated proteins, while inhibiting vascular permeability and reducing endothelial cell apoptosis. This ultimately mitigated behavioral deficits in PT stroke rats. Notably, treatment with the androgen receptor antagonist flutamide reversed the beneficial effects of PBMT. Cellular experiments confirmed that PBMT inhibited cell apoptosis and increased vascular-associated protein expression in brain endothelial cell line (bEnd.3) subjected to oxygen-glucose deprivation (OGD). However, these effects were inhibited by flutamide. Moreover, mechanistic studies revealed that PBMT-induced testosterone synthesis in bEnd.3 cells was partly mediated by 17ß-hydroxysteroid dehydrogenase 5 (17ß-HSD5). CONCLUSIONS: Our study provides evidence that PBMT attenuates cerebrovascular injury and behavioral deficits associated with testosterone/AR following ischemic stroke. Our findings suggest that PBMT may be a promising alternative approach for managing cerebrovascular diseases.

Enhancing axonal myelination: Clemastine attenuates cognitive impairment in a rat model of diffuse traumatic brain injury.

Traumatic brain injury (TBI) has a significant impact on cognitive function, affecting millions of people worldwide. Myelin loss is a prominent pathological feature of TBI, while well-functioning myelin is crucial for memory and cognition. Utilizing drug repurposing to identify effective drug candidates for TBI treatment has gained attention. Notably, recent research has highlighted the potential of clemastine, an FDA-approved allergy medication, as a promising pro-myelinating drug. Therefore, in this study, we aim to investigate whether clemastine can enhance myelination and alleviate cognitive impairment following mild TBI using a clinically relevant rat model of TBI. Mild diffuse TBI was induced using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Animals were treated with either clemastine or an equivalent volume of the vehicle from day 1 to day 14 post-injury. Following treatment, memory-related behavioral tests were conducted, and myelin pathology in the cortex and hippocampus was assessed through immunofluorescence staining and ProteinSimple® capillary-based immunoassay. Our results showed that TBI leads to significant myelin loss, axonal damage, glial activation, and a decrease in mature oligodendrocytes in both the cortex and hippocampus. The TBI animals also exhibited notable deficits in memory-related tests. In contrast, animals treated with clemastine showed an increase in mature oligodendrocytes, enhanced myelination, and improved performance in the behavioral tests. These preliminary findings support the therapeutic value of clemastine in alleviating TBI-induced cognitive impairment, with substantial clinical translational potential. Our findings also underscore the potential of remyelinating therapies for TBI.

Photobiomodulation attenuates oligodendrocyte dysfunction and prevents adverse neurological consequences in a rat model of early life adversity.

Rationale: Adverse experiences in early life including abuse, trauma and neglect, have been linked to poor physical and mental health outcomes. Emerging evidence implies that those who experienced early life adversity (ELA) are more likely to develop cognitive dysfunction and depressive-like symptoms in adulthood. The molecular mechanisms responsible for the negative consequences of ELA, however, remain unclear. In the absence of effective management options, anticipatory guidance is the mainstay of ELA prevention. Furthermore, there is no available treatment that prevents or alleviates the neurologic sequelae of ELA, especially traumatic stress. Hence, the present study aims to investigate the mechanisms for these associations and evaluate whether photobiomodulation (PBM), a non-invasive therapeutic procedure, can prevent the negative cognitive and behavioral manifestations of ELA in later life. Methods: ELA was induced by repeated inescapable electric foot shock of rats from postnatal day 21 to 26. On the day immediately following the last foot shock, 2-min daily PBM treatment was applied transcranially for 7 consecutive days. Cognitive dysfunction and depression-like behaviors were measured by a battery of behavioral tests in adulthood. Subsequently, oligodendrocyte progenitor cells (OPCs) differentiation, the proliferation and apoptosis of oligodendrocyte lineage cells (OLs), mature oligodendrocyte, myelinating oligodendrocyte, the level of oxidative damage, reactive oxygen species (ROS) and total antioxidant capacity were measured and analyzed using immunofluorescence staining, capillary-based immunoassay (ProteinSimple®) and antioxidant assay kit. Results: The rats exposed to ELA exhibited obvious oligodendrocyte dysfunction, including a reduction in OPCs differentiation, diminished generation and survival of OLs, decreased OLs, and decreased matured oligodendrocyte. Furthermore, a deficit in myelinating oligodendrocytes was observed, in conjunction with an imbalance in redox homeostasis and accumulated oxidative damage. These alternations were concomitant with cognitive dysfunction and depression-like behaviors. Importantly, we found that early PBM treatment largely prevented these pathologies and reversed the neurologic sequelae resulting from ELA. Conclusions: Collectively, these findings provide new insights into the mechanism by which ELA affects neurological outcomes. Moreover, our findings support that PBM may be a promising strategy to prevent ELA-induced neurologic sequelae that develops later in life.

Overexpression of vascular endothelial growth factor enhances the neuroprotective effects of bone marrow mesenchymal stem cell transplantation in ischemic stroke.

Although bone marrow mesenchymal stem cells (BMSCs) might have therapeutic potency in ischemic stroke, the benefits are limited. The current study investigated the effects of BMSCs engineered to overexpress vascular endothelial growth factor (VEGF) on behavioral defects in a rat model of transient cerebral ischemia, which was induced by middle cerebral artery occlusion. VEGF-BMSCs or control grafts were injected into the left striatum of the infarcted hemisphere 24 hours after stroke. We found that compared with the stroke-only group and the vehicle- and BMSCs-control groups, the VEGF-BMSCs treated animals displayed the largest benefits, as evidenced by attenuated behavioral defects and smaller infarct volume 7 days after stroke. Additionally, VEGF-BMSCs greatly inhibited destruction of the blood-brain barrier, increased the regeneration of blood vessels in the region of ischemic penumbra, and reducedneuronal degeneration surrounding the infarct core. Further mechanistic studies showed that among all transplant groups, VEGF-BMSCs transplantation induced the highest level of brain-derived neurotrophic factor. These results suggest that BMSCs transplantation with vascular endothelial growth factor has the potential to treat ischemic stroke with better results than are currently available.

Photobiomodulation treatment inhibits neurotoxic astrocytic polarization and protects neurons in in vitro and in vivo stroke models.

The beneficial effects of photobiomodulation (PBM) on function recovery after stroke have been well-established, while its molecular and cellular mechanisms remain to be elucidated. The current study was designed to investigate the effect of PBM on synaptic proteins and astrocyte polarization of photothrombotic (PT)-stroke induced rats in vivo, and explore the possible effect of PBM treatment on oxygen-glucose deprivation (OGD)-induced neurotoxic astrocytic polarization in vitro. We reported that 2-min PBM treatment (808 nm) for 7 days significantly increased synaptic proteins and neuroprotective astrocytic marker S100 Calcium Binding Protein A10 (S100A10) and inhibited neurotoxic astrocytic marker C3d in the peri-infarct region after ischemic stroke. Cell culture studies of primary cortical neurons and N2a cells showed that single-dose PBM treatment could increase cellular viability, regulate the apoptotic proteins (Caspase 9, Bcl-xL and BAX) and preserve synaptic proteins following OGD exposure. Additionly, PBM decreased the levels of C3d, inducible nitric oxide synthase (iNOS) and interleukin 1ß (IL-1ß) on astrocytes exposed to OGD. In summary, we demonstrated that PBM could inhibit neurotoxic astrocytic polarization, preserve synaptic integrity and protect neurons against stroke injury both in vitro and in vivo.

Targeting Alzheimer's Disease: The Critical Crosstalk between the Liver and Brain.

Alzheimer's disease (AD), an age-related neurodegenerative disorder, is currently incurable. Imbalanced amyloid-beta (Aß) generation and clearance are thought to play a pivotal role in the pathogenesis of AD. Historically, strategies targeting Aß clearance have typically focused on central clearance, but with limited clinical success. Recently, the contribution of peripheral systems, particularly the liver, to Aß clearance has sparked an increased interest. In addition, AD presents pathological features similar to those of metabolic syndrome, and the critical involvement of brain energy metabolic disturbances in this disease has been recognized. More importantly, the liver may be a key regulator in these abnormalities, far beyond our past understanding. Here, we review recent animal and clinical findings indicating that liver dysfunction represents an early event in AD pathophysiology. We further propose that compromised peripheral Aß clearance by the liver and aberrant hepatic physiological processes may contribute to AD neurodegeneration. The role of a hepatic synthesis product, fibroblast growth factor 21 (FGF21), in the management of AD is also discussed. A deeper understanding of the communication between the liver and brain may lead to new opportunities for the early diagnosis and treatment of AD.

Continuous theta-burst stimulation enhances and sustains neurogenesis following ischemic stroke.

Rationale: Previous work has indicated that continuous theta-burst stimulation (cTBS), a modality of transcranial magnetic stimulation (TMS), may provide neuroprotection and improve neurological function after stroke by preserving the blood-brain barrier, altering glial polarization phenotypes, and supporting peri-infarct angiogenesis. The present study was performed to examine whether cTBS, a noninvasive neurostimulation technique, promotes neurogenesis in a photothrombotic (PT) stroke rat model and contributes to functional recovery. Methods: Beginning 3 h or 1 week after the induction of PT stroke, once-daily 5-min cTBS treatments were applied to the infarcted hemisphere for 6 days. Samples were collected 6 days, 22 days, and 35 days after PT stroke. Fluorescent labeling, Western blotting, and behavioral tests were performed accordingly. Results: We found that cTBS therapy significantly expanded the pool of neural progenitor cells (NPCs) and newly generated immature neurons in the cortical peri-infarct region after PT stroke. Likewise, the amount of DCX-positive immature neurons in the peri-infarct area was markedly elevated by cTBS. Application of cTBS strikingly diminished the PT-induced loss of NPCs and newly-formed neurons. In addition, the amount of newly generated mature neurons in the peri-infarct zone was significantly promoted by cTBS. Intriguingly, cTBS reduced reactive gliogenesis significantly while promoting oligodendrogenesis and preserving myelination. Mechanistic studies uncovered that cTBS upregulated brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2). Finally, cTBS-treated animals displayed improved motor functions. To be noted, temozolomide (TMZ), a drug that has been previously used to suppress neurogenesis, could reverse the beneficial effects of cTBS. Conclusions: Our findings provide new insight into the mechanism by which cTBS promotes functional recovery from stroke. We demonstrated that cTBS effectively enhances and sustains neurogenesis after PT stroke. Both early and delayed cTBS treatment could improve the survival of newly generated neurons and functional recovery, and inhibition of neurogenesis could reverse these therapeutic benefits. Mechanistically, cTBS was effective in upregulating the release of neurotrophic factors, protecting NPC and immature neurons, as well as suppressing excessive gliogenesis.

Long-Term Variations in Global Solar Radiation and Its Interaction with Atmospheric Substances at Qomolangma.

An empirical model to estimate global solar radiation was developed at Qomolangma Station using observed solar radiation and meteorological parameters. The predicted hourly global solar radiation agrees well with observations at the ground in 2008-2011. This model was used to calculate global solar radiation at the ground and its loss in the atmosphere due to absorbing and scattering substances in 2007-2020. A sensitivity analysis shows that the responses of global solar radiation to changes in water vapor and scattering factors (expressed as water-vapor pressure and the attenuation factor, AF, respectively) are nonlinear, and global solar radiation is more sensitive to changes in scattering than to changes in absorption. Further applying this empirical model, the albedos at the top of the atmosphere (TOA) and the surface in 2007-2020 were computed and are in line with satellite-based retrievals. During 2007-2020, the mean estimated annual global solar radiation increased by 0.22% per year, which was associated with a decrease in AF of 1.46% and an increase in water-vapor pressure of 0.37% per year. The annual mean air temperature increased by about 0.16 °C over the 14 years. Annual mean losses of solar radiation caused by absorbing and scattering substances and total loss were 2.55, 0.64, and 3.19 MJ m-2, respectively. The annual average absorbing loss was much larger than the scattering loss; their contributions to the total loss were 77.23% and 22.77%, indicating that absorbing substances play significant roles. The annual absorbing loss increased by 0.42% per year, and scattering and total losses decreased by 2.00% and 0.14% per year, respectively. The estimated and satellite-derived annual albedos increased at the TOA and decreased at the surface. This study shows that solar radiation and its interactions with atmospheric absorbing and scattering substances have played key but different roles in regional climate and climate change at the three poles.

Repetitive transcranial magnetic stimulation (rTMS) for multiple neurological conditions in rodent animal models: A systematic review.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique. Recently, rTMS has shown promising therapeutic potential in multiple neurological conditions. Nevertheless, challenges remain in the clinical application of rTMS, which mainly due to the lack of consensus on optimal stimulation protocols and poor understanding of the exact targets driving its action. Experimental animal research with more controllable factors may contribute to fill our knowledge gap in this area, and to accelerate the development of clinical translation studies. Therefore, the current study was designed to systematically review the effects of rTMS on animal models of certain diseases and evaluate its potential mechanisms of action, which may guide future studies aiming to improve the therapeutic utilization for these diseases. METHODS: A systematic literature search was conducted through the PubMed online database on August 19, 2021. The search strategy consisted of two main components: rTMS and stroke, Alzheimer's disease (AD), vascular dementia (VaD), and Parkinson's disease (PD), with results limited to animal studies. RESULTS: We identified 41 animal studies, 21 that examined stroke, 8 that investigated Alzheimer's disease, 5 that studied vascular dementia, and 7 that examined Parkinson's disease, all of these studies were conducted in rodents (rat and mice). Despite variations in study design and research methods, the therapeutic benefits of rTMS, as reflected in the alleviation of disease-related symptoms and pathological improvements, have been reported in these studies. rTMS induces multi-directional changes at the cellular and molecular levels, including a significant contribution to synaptic plasticity. Furthermore, the curative effects of rTMS are related to stimulation parameters, with high-frequency rTMS reported has better therapeutic efficacy in several studies. In terms of safety, one study involving combination therapy reported the adverse effects of rTMS administration. CONCLUSIONS: rTMS have shown encouraging therapeutic value in rodent models of stroke, AD, VaD, and PD. Nonetheless, the optimal protocols and exact target of action for this therapy remain to be determined. Correspondingly, further research is still needed to bridge the translation gap between rodent experiments and clinical application, which might lead to new directions in the treatment of multiple neurological disorders.

Long-Term Variations of Global Solar Radiation and Its Potential Effects at Dome C (Antarctica).

An empirical model to predict hourly global solar irradiance under all-sky conditions as a function of absorbing and scattering factors has been applied at the Dome C station in the Antarctic, using measured solar radiation and meteorological variables. The calculated hourly global solar irradiance agrees well with measurements at the ground in 2008-2011 (the model development period) and at the top of the atmosphere (TOA). This model is applied to compute global solar irradiance at the ground and its extinction in the atmosphere caused by absorbing and scattering substances during the 2006-2016 period. A sensitivity study shows that the responses of global solar irradiance to changes in water vapor and scattering factors (expressed by water vapor pressure and S/G, respectively; S and G are diffuse and global solar irradiance, respectively) are nonlinear and negative, and that global solar irradiance is more sensitive to changes in scattering than to changes in water vapor. Applying this empirical model, the albedos at the TOA and the surface in 2006-2016 are estimated and found to agree with the satellite-based retrievals. During 2006-2016, the annual mean observed and estimated global solar exposures decreased by 0.05% and 0.09%, respectively, and the diffuse exposure increased by 0.68% per year, associated with the yearly increase of the S/G ratio by 0.57% and the water vapor pressure by 1.46%. The annual mean air temperature increased by about 1.80 °C over the ten years, and agrees with the warming trends for all of Antarctica. The annual averages were 316.49 Wm-2 for the calculated global solar radiation, 0.332 for S/G, -46.23 °C for the air temperature and 0.10 hPa for the water vapor pressure. The annual mean losses of solar exposure due to absorbing and scattering substances and the total loss were 4.02, 0.19 and 4.21 MJ m-2, respectively. The annual mean absorbing loss was much larger than the scattering loss; their contributions to the total loss were 95.49% and 4.51%, respectively, indicating that absorbing substances are dominant and play essential roles. The annual absorbing, scattering and total losses increased by 0.01%, 0.39% and 0.28% per year, respectively. The estimated and satellite-retrieved annual albedos increased at the surface. The mechanisms of air-temperature change at two pole sites, as well as a mid-latitude site, are discussed.

Curcumin ameliorates ischemic stroke injury in rats by protecting the integrity of the blood-brain barrier.

The blood-brain barrier (BBB) is critical for proper cerebral homeostasis and its dysfunction during ischemic stroke can result in significant neurological injury. The major goal of the present study was to identify whether curcumin pretreatment possessed protective effects on BBB integrity during the 24 h of acute ischemic brain injury. To investigate the protective effects of curcumin, male Sprague-Dawley rats were divided into multiple groups, including sham, middle cerebral artery occlusion/reperfusion (MCAO/R) vehicle and curcumin pretreated MCAO/R groups. The effects of curcumin were measured by analyzing neurological deficits, infarct size, BBB permeability and expression levels of permeability-related proteins in the brain. It was found that curcumin pretreatment significantly improved neurological scores, decreased infarct size, and protected synaptic remodeling of hippocampal neurons and upregulated the protein expression level of tight junction proteins, ZO-1, occludin and claudin-5 in ischemic rat brains. Furthermore, curcumin pretreatment before stroke was shown to downregulate the phosphorylation of NF-κB and MMP-9, which are central mediators of inflammation. The results from the present study indicated that curcumin pretreatment ameliorated ischemic stroke injury by protecting BBB integrity and synaptic remodeling, as well as inhibiting inflammatory responses.

Transcranial photobiomodulation prevents PTSD-like comorbidities in rats experiencing underwater trauma.

Maladaptive fear memory processing after a traumatic event is a major contributor to the development of the comorbidities related to posttraumatic stress disorder (PTSD). An intervention to normalize this process could be a first-line treatment to prevent PTSD development. However, little progress has been made in identifying interventions that can prevent trauma survivors from developing PTSD. A treatment that could help trauma survivors cope with traumatic memories and decrease the prevalence of PTSD is thus in high demand. This study was designed to investigate the potential beneficial effects of early photobiomodulation (PBM) interventions to prevent PTSD-like comorbidities in animals. PTSD-like comorbidities in rats were induced by an underwater trauma (UWT) procedure, followed by multiple swimming sessions on later days for memory recall. Immediately after UWT and swimming, rats were restrained with or without PBM treatment (808 nm, 25 mW/cm2, 3 J/day). PTSD-like commodities, such as anxiety-like behavior, depression-like behavior, and cognitive dysfunction, were reproduced in UWT-rats. These comorbidities, however, could be prevented by early PBM interventions. By measuring the expression of immediate early genes (IEGs) as neuronal activity markers, we found that PBM treatment differentially regulated Arc and c-fos expression in the hippocampus and amygdala, two PTSD-related brain regions. Additionally, PBM boosted ATP production and regulated protein expression in the hippocampus following stress. Our results demonstrate that PBM can modulate brain activity in response to traumatic and stressful events and that early PBM intervention can prevent the occurrence of PTSD-like comorbidities in rats.

Photobiomodulation prevents PTSD-like memory impairments in rats.

A precise fear memory encoding a traumatic event enables an individual to avoid danger and identify safety. An impaired fear memory (contextual amnesia), however, puts the individual at risk of developing posttraumatic stress disorder (PTSD) due to the inability to identify a safe context when encountering trauma-associated cues later in life. Although it is gaining attention that contextual amnesia is a critical etiologic factor for PTSD, there is no treatment currently available that can reverse contextual amnesia, and whether such treatment can prevent the development of PTSD is unknown. Here, we report that (I) a single dose of transcranial photobiomodulation (PBM) applied immediately after tone fear conditioning can reverse contextual amnesia. PBM treatment preserved an appropriately high level of contextual fear memory in rats revisiting the "dangerous" context, while control rats displayed memory impairment. (II) A single dose of PBM applied after memory recall can reduce contextual fear during both contextual and cued memory testing. (III) In a model of complex PTSD with repeated trauma, rats given early PBM interventions efficiently discriminated safety from danger during cued memory testing and, importantly, these rats did not develop PTSD-like symptoms and comorbidities. (IV) Finally, we report that fear extinction was facilitated when PBM was applied in the early intervention window of memory consolidation. Our results demonstrate that PBM treatment applied immediately after a traumatic event or its memory recall can protect contextual fear memory and prevent the development of PTSD-like psychopathological fear in rats.

Effects of prenatal photobiomodulation treatment on neonatal hypoxic ischemia in rat offspring.

Neonatal hypoxic-ischemic (HI) injury is a severe complication often leading to neonatal death and long-term neurobehavioral deficits in children. Currently, the only treatment option available for neonatal HI injury is therapeutic hypothermia. However, the necessary specialized equipment, possible adverse side effects, and limited effectiveness of this therapy creates an urgent need for the development of new HI treatment methods. Photobiomodulation (PBM) has been shown to be neuroprotective against multiple brain disorders in animal models, as well as limited human studies. However, the effects of PBM treatment on neonatal HI injury remain unclear. Methods: Two-minutes PBM (808 nm continuous wave laser, 8 mW/cm2 on neonatal brain) was applied three times weekly on the abdomen of pregnant rats from gestation day 1 (GD1) to GD21. After neonatal right common carotid artery ligation, cortex- and hippocampus-related behavioral deficits due to HI insult were measured using a battery of behavioral tests. The effects of HI insult and PBM pretreatment on infarct size; synaptic, dendritic, and white matter damage; neuronal degeneration; apoptosis; mitochondrial function; mitochondrial fragmentation; oxidative stress; and gliosis were then assessed. Results: Prenatal PBM treatment significantly improved the survival rate of neonatal rats and decreased infarct size after HI insult. Behavioral tests revealed that prenatal PBM treatment significantly alleviated cortex-related motor deficits and hippocampus-related memory and learning dysfunction. In addition, mitochondrial function and integrity were protected in HI animals treated with PBM. Additional studies revealed that prenatal PBM treatment significantly alleviated HI-induced neuroinflammation, oxidative stress, and myeloid cell/astrocyte activation. Conclusion: Prenatal PBM treatment exerts neuroprotective effects on neonatal HI rats. Underlying mechanisms for this neuroprotection may include preservation of mitochondrial function, reduction of inflammation, and decreased oxidative stress. Our findings support the possible use of PBM treatment in high-risk pregnancies to alleviate or prevent HI-induced brain injury in the perinatal period.

Theta-burst transcranial magnetic stimulation promotes stroke recovery by vascular protection and neovascularization.

Rationale: The integrity and function of the blood-brain barrier (BBB) is compromised after stroke. The current study was performed to examine potential beneficial effects and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) on angiogenesis and vascular protection, function, and repair following stroke, which are largely unknown. Methods: Using a rat photothrombotic (PT) stroke model, continuous theta-burst rTMS was administered once daily to the infarcted hemisphere for 5 min, beginning 3 h after PT stroke. This treatment was applied for 6 days. BBB integrity, blood flow, vascular associated proteins, angiogenesis, integrity of neuronal morphology and structure, and behavioral outcome were measured and analyzed at 6 and/or 22 days after PT stroke. Results: We report that rTMS significantly mitigated BBB permeabilization and preserved important BBB components ZO-1, claudin-5, occludin, and caveolin-1 from PT-induced degradation. Damage to vascular structure, morphology, and perfusion was ameliorated by rTMS, resulting in improved local tissue oxygenation. This was accompanied with robust protection of critical vascular components and upregulation of regulatory factors. A complex cytokine response was induced by PT, particularly at the late phase. Application of rTMS modulated this response, ameliorating levels of cytokines related to peripheral immune cell infiltration. Further investigation revealed that rTMS promoted and sustained post-ischemic angiogenesis long-term and reduced apoptosis of newborn and existing vascular endothelial cells. Application of rTMS also inhibited PT-induced excessive astrocyte-vasculature interactions and stimulated an A1 to A2 shift in vessel-associated astrocytes. Mechanistic studies revealed that rTMS dramatically increased levels of PDGFRß associated with A2 astrocytes and their adjacent vasculature. As well, A2 astrocytes displayed marked amplification of the angiogenesis-related factors VEGF and TGFß. PT induced a rise in vessel-associated expression of HIF-1α that was starkly intensified by rTMS treatment. Finally, rTMS preserved neuronal morphology, synaptic structure integrity and behavioral outcome. Conclusions: These results indicate that rTMS can exert powerful protective and restorative effects on the peri-infarct microvasculature after PT stroke by, in part, promoting HIF-1α signaling and shifting vessel-associated astrocytic polarization to the A2 phenotype. This study provides further support for the potent protective effects of rTMS in the context of ischemic stroke, and these findings implicate vascular repair and protection as an important underlying phenomenon.

Potential value of guard-wire technology in the interventional treatment for ostial coronary lesions.

BACKGROUND: To explore potential value of guard-wire technology during percutaneous coronary intervention (PCI) in patients with ostial coronary lesions. METHODS: Patients, who underwent PCI, were collected between October 2011 and March 2017. Of the 141 patients, 63 (44.7%) have ostial lesions, and 78 (55.3%) have distal bifurcation sites. They were divided into group A (n = 71) and group B (n = 70). Group A received PCI after guard-wire technology. Group B were given balloon dilation and stent after placing guide wire through target lesion vessel. X-ray exposure time, contrast agent dosage, total PCI duration, pressure incarceration times, cases of malignant arrhythmia and cases of failed PCI of all patients were analyzed, respectively. RESULTS: The general clinical characteristics includes patients age, sex ratio, the proportion of complications, smoking ratio and left ventricular ejection fraction of both groups was not significantly different. X-ray exposure time, contrast agent dosage, PCI total time, stent positioning time, pressure infestation frequency, arrhythmia frequency and complication number of group B were higher than those of group A. There is no case of malignant arrhythmia and case of failed PCI in group A, while there were five malignant arrhythmia and four failed PCI in group B. Contrast agent dosage and cases of failed PCI increased in group B compared with group A. CONCLUSION: The guard wire technology is safer and more feasible to patients with ostial coronary lesions who underwent PCI.

Effects of Exercise Training on Anxious-Depressive-like Behavior in Alzheimer Rat.

PURPOSE: This study aimed to examine the effects of treadmill training on anxious-depressive-like behaviors of transgenic Alzheimer rats in the early stage of Alzheimer's disease (AD) and provided evidence of exercise in alleviating fear-avoidance behavior deficits. METHODS: Male 2-month-old TgF344-AD and wild-type rats were divided into wild-type (n = 9), AD (n = 8), and AD + treadmill exercise (Exe) groups (n = 12). After 8 months of exercise, the passive avoidance test, Barnes maze task, novel object recognition test, and object location test were used to measure learning and memory function. The open-field test, elevated plus maze, sucrose preference test, and forced swim test were conducted to determine the anxious-depressive-like behavior of AD rats. Immunofluorescence staining, Western blot analysis, enzyme-linked immunosorbent assay analysis, and related assay kits were used to measure inflammatory cytokines, oxidative stress, amyloid-ß production, and tau hyperphosphorylation. RESULTS: Behavioral tests revealed that 12-month-old animals did not show any spatial learning and memory deficits but did display anxious-depressive-like behavior (open field, center time: P = 0.008; center entries: P = 0.009; line crossings: P = 0.001). However, long-term exercise significantly inhibited anxious-depressive-like behavior in AD rats (center time: P = 0.016; center entries: P = 0.004; line crossings: P = 0.033). In addition, these animals displayed increased amyloid-ß deposition, tau hyperphosphorylation, microgliosis, inflammatory cytokines release, and oxidative damage, which were attenuated significantly by long-term exercise training. CONCLUSION: Long-term exercise training alleviated anxious-depressive-like behavior and improved fear-avoidance behavior in transgenic AD rats, supporting exercise training as an effective approach to prevent anxiety, depression, and fear-avoidance behavior deficits in the early stages of AD pathogenesis.

Beneficial Effects of Theta-Burst Transcranial Magnetic Stimulation on Stroke Injury via Improving Neuronal Microenvironment and Mitochondrial Integrity.

Recent work suggests that repetitive transcranial magnetic stimulation (rTMS) may beneficially alter the pathological status of several neurological disorders, although the mechanism remains unclear. The current study was designed to investigate the effects of rTMS on behavioral deficits and potential underlying mechanisms in a rat photothrombotic (PT) stroke model. From day 0 (3 h) to day 5 after the establishment of PT stroke, 5-min daily continuous theta-burst rTMS (3 pulses of 50 Hz repeated every 200 ms, intensity at 200 G) was applied on the infarct hemisphere. We report that rTMS significantly attenuated behavioral deficits and infarct volume after PT stroke. Further investigation demonstrated that rTMS remarkably reduced synaptic loss and neuronal degeneration in the peri-infarct cortical region. Mechanistic studies displayed that beneficial effects of rTMS were associated with robust suppression of reactive micro/astrogliosis and the overproduction of pro-inflammatory cytokines, as well as oxidative stress and oxidative neuronal damage especially at the late stage following PT stroke. Intriguingly, rTMS could effectively induce a shift in microglial M1/M2 phenotype activation and an A1 to A2 switch in astrocytic phenotypes. In addition, the release of anti-inflammatory cytokines and mitochondrial MnSOD in peri-infarct regions were elevated following rTMS treatment. Finally, rTMS treatment efficaciously preserved mitochondrial membrane integrity and suppressed the intrinsic mitochondrial caspase-9/3 apoptotic pathway within the peri-infarct cortex. Our novel findings indicate that rTMS treatment exerted robust neuroprotection when applied at least 3 h after ischemic stroke. The underlying mechanisms are partially associated with improvement of the local neuronal microenvironment by altering inflammatory and oxidative status and preserving mitochondrial integrity in the peri-infarct zone. These findings provide strong support for the promising therapeutic effect of rTMS against ischemic neuronal injury and functional deficits following stroke.