GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer's disease mouse model.

GV1001 protects neural cells from amyloid-ß (Aß) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer's disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aß oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aß oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.

Effect of Penetration Enhancers on Toenail Delivery of Efinaconazole from Hydroalcoholic Preparations.

The incorporation of permeation enhancers in topical preparations has been recognized as a simple and valuable approach to improve the penetration of antifungal agents into toenails. In this study, to improve the toenail delivery of efinaconazole (EFN), a triazole derivative for onychomycosis treatment, topical solutions containing different penetration enhancers were designed, and the permeation profiles were evaluated using bovine hoof models. In an in vitro permeation study in a Franz diffusion cell, hydroalcoholic solutions (HSs) containing lipophilic enhancers, particularly prepared with propylene glycol dicaprylocaprate (Labrafac PG), had 41% higher penetration than the HS base. Moreover, the combination of hydroxypropyl-ß-cyclodextrin with Labrafac PG further facilitated the penetration of EFN across the hoof membrane. In addition, this novel topical solution prepared with both lipophilic and hydrophilic enhancers was physicochemically stable, with no drug degradation under ambient conditions (25 °C, for 10 months). Therefore, this HS system can be a promising tool for enhancing the toenail permeability and therapeutic efficacy of EFN.

Terahertz continuous wave system using phase shift interferometry for measuring the thickness of sub-100-µm-thick samples without frequency sweep.

A terahertz continuous wave system is demonstrated for thickness measurement using Gouy phase shift interferometry without frequency sweep. One arm of the interferometer utilizes a collimated wave as a reference, and the other arm applies a focused beam for sample investigation. When the optical path difference (OPD) of the arms is zero, a destructive interference pattern is produced. Interference signal intensity changes induced by the OPD changes can be easily predicted by calculations. By minimizing the difference between the measured and the calculated signal against the OPD, the thicknesses of sub-100-µm-thick samples are determined at 625 GHz.

Relationship between cerebral microbleeds and white matter MR hyperintensities in systemic lupus erythematosus: a retrospective observational study.

PURPOSE: White matter hyperintensities (WMH) and cerebral microbleeds (CMBs) are known to be associated with small vessel diseases (SVD) and neuroinflammation. The purpose was to investigate the relationship between CMBs and WMH in patients with systemic lupus erythematosus (SLE). METHODS: Thirty-one SLE patients with WMH and 27 SLE patients with normal brain MRI were compared. The presence, location, and grading of CMBs were assessed using susceptibility-weighted images. WMH volume was quantitatively measured. Clinical characteristics and serologic markers were compared. We also performed two separate subgroup analyses after (1) dividing WMH into inflammatory lesion vs. SVD subgroups and (2) dividing WMH into those with vs. without CMB subgroups. RESULTS: The WMH group showed more frequent CMBs than the normal MR group (p < 0.001). The WMH group showed higher SLE disease activity index, longer disease duration, and a higher incidence of antiphospholipid syndrome than the normal MR group (p = 0.02, 0.04, and 0.04, respectively). There was a moderate correlation between WMH volume and CMB grading (r = 0.49, p = 0.006). Within the WMH group, the inflammatory lesion subgroup showed more frequent CMBs and larger WMH volume than the SVD subgroup (p < 0.001 and 0.02, respectively). The WMH with CMB subgroup had larger WMH volume than the WMH without CMB subgroup (p = 0.004). CONCLUSION: In patients with SLE, CMBs could be related to large-volume WMH and inflammatory lesions. CMBs along with severe WMH could be used as an imaging biomarker of vasculitis in patients with SLE.

The clinical value of 4-hour delayed-enhanced 3D-FLAIR MR images in sudden hearing loss.

OBJECTIVE: The aim of this study was to investigate the clinical significance of 4-hour delayed-enhanced 3.0 Tesla (3T) 3D-fluid-attenuated inversion recovery (FLAIR) MR imaging in sudden sensorineural hearing loss (SSNHL). STUDY DESIGN: Case series with comparisons. SETTING: Tertiary referral centre. PARTICIPANTS: Eighty-seven idiopathic SSNHL patients were enrolled between January 2015 and December 2016 and received high dose steroid therapy and intratympanic steroid injections as salvage treatment. INTERVENTION: Pre-contrast, 10-minute and 4-hour delayed-enhanced 3D-FLAIR MR images were obtained using double-dose IV gadolinium. MAIN OUTCOME MEASURES: The results of treatment were evaluated according to Siegel's criteria 3 months after the start of treatment. Where possible lesion-side laterality of the inner ear was identified based on the MR images, the associations between MR findings and other clinical parameters were analysed, and the relationships between hearing recovery and MR image findings were assessed. RESULTS: Lesion-side laterality was identified on MRI in 52 (59.7%), 18 (20.1%) and 8 (9.2%) patients, based on 4-hour delayed, 10-minute delayed, and pre-contrast images, respectively. The hearing recovery rate was significantly lower in the patients with lesion-side laterality on 4-hour delayed images (P < 0.001). In a multivariate analysis, lesion-side laterality on 4-hour delayed images was associated with poor prognosis (OR = 5.6) after adjusting other prognostic factors including initial hearing level, lesion-side laterality on 10-min delayed images and presence of vertigo. In addition, as the extent of enhancement in the inner ear increased the probability of hearing recover decreased (P = 0.001). CONCLUSIONS: Contrast enhancement of inner ear structures can be seen on 4-hour delayed-enhanced 3T 3D-FLAIR MR images in idiopathic SSNHL. Asymmetric lesion-side enhancement of the inner ear may be associated with a poor prognosis.

Terahertz rectifier exploiting electric field-induced hot-carrier effect in asymmetric nano-electrode.

Rectifiers have been used to detect electromagnetic waves with very low photon energies. In these rectifying devices, different methods have been utilized, such as adjusting the bandgap and the doping profile, or utilizing the contact potential of the metal-semiconductor junction to produce current flow depending on the direction of the electric field. In this paper, it is shown that the asymmetric application of nano-electrodes to a metal-semiconductor-metal (MSM) structure can produce such rectification characteristics, and a terahertz (THz) wave detector based on the nano-MSM structure is proposed. Integrated with a receiving antenna, the fabricated device detects THz radiation up to a frequency of 1.5 THz with responsivity and noise equivalent power of 10.8 V/W and [Formula: see text] respectively, estimated at 0.3 THz. The unidirectional current flow is attributed to the thermionic emission of hot carriers accelerated by the locally enhanced THz field at the sharp end of the nano-electrode. This work not only demonstrates a new type of THz detector but also proposes a method for manipulating ultrafast charge-carrier dynamics through the field enhancement of the nano-electrode, which can be applied to ultrafast photonic and electronic devices.

Quantitative susceptibility mapping of the motor cortex: a comparison of susceptibility among patients with amyotrophic lateral sclerosis, cerebrovascular disease, and healthy controls.

PURPOSE: The purpose of this study was to investigate the differences in motor cortex susceptibility among patients with amyotrophic lateral sclerosis (ALS), cerebrovascular disease (CVD), and healthy controls using quantitative susceptibility mapping (QSM). METHODS: We retrospectively reviewed 78 QSM images from 26 patients with ALS, 26 age- and sex-matched patients with CVD, and 26 healthy controls. A region of interest was drawn in the hand lobule of both the motor cortexes and subcortical white matter. The relative susceptibility (RS) of the motor cortex was obtained by subtracting the susceptibility of the subcortical white matter from that of the motor cortex. We compared the cortexmean, cortexmax, subcortical white mattermean, RSmean, and RSmax values among the three groups using analysis of variance and Tukey's post hoc test. Receiver operating characteristic (ROC) curve analysis was also performed. RESULTS: There were significant differences in the cortexmean, cortexmax, RSmean, and RSmax among the three groups, with higher values in patients with ALS (p = 0.01, p = 0.004, p < 0.001, and p < 0.001, respectively). Subcortical white mattermean was significantly lower in patients with ALS compared with patients with CVD and healthy controls (p = 0.04). ROC curve analysis showed that the area under the curve of RSmean was 0.70, the highest among the measured parameters. CONCLUSION: Quantitative measurements of susceptibility of the motor cortex with QSM demonstrate its potential as an imaging biomarker in ALS patients.

Noninfectious Meningitis Caused by Systemic Lupus Erythematosus: A Case Series of 4 Patients.

We report magnetic resonance imaging findings of 4 patients with systemic lupus erythematosus who presented with noninfectious meningitis by lupus itself. Magnetic resonance imaging of the brain demonstrated diffuse or localized high-signal intensity in subarachnoid spaces on fluid-attenuated inversion recovery (FLAIR) or postcontrast fluid-attenuated inversion recovery. Cerebrospinal fluid study revealed no abnormalities other than increased level of proteins. Our report is the first description of magnetic resonance findings in context of leptomeningeal involvement in non-infectious meningitis of patients with systemic lupus erythematosus.

GV1001 reduces neurodegeneration and prolongs lifespan in 3xTg-AD mouse model through anti-aging effects.

GV1001, which mimics the activity of human telomerase reverse transcriptase, protects neural cells from amyloid beta (Aß) toxicity and other stressors through extra-telomeric function, as noted in our prior in vitro studies. As per a recent phase II clinical trial, it improves cognitive function in patients with moderate to severe dementia. However, the underlying protective mechanisms remain unclear. This study aimed to investigate the effects of GV1001 on neurodegeneration, senescence, and survival in triple transgenic Alzheimer's disease (3xTg-AD) mice. GV1001 (1 mg/kg) was subcutaneously injected into old 3xTg-AD mice thrice a week until the endpoint for sacrifice, and survival was analysed. Magnetic resonance imaging (MRI) and Prussian blue staining (PBS) were performed to evaluate entry of GV1001 entrance into the brain. Diverse molecular studies were performed to investigate the effect of GV1001 on neurodegeneration and cellular senescence in AD model mice, with a particular focus on BACE, amyloid beta1-42 (Aß1-42), phosphorylated tau, volume of dentate gyrus, ß-galactosidase positive cells, telomere length, telomerase activity, and ageing-associated proteins. GV1001 crossed the blood-brain barrier, as confirmed by assessing the status of ferrocenecarboxylic acid-conjugated GV1001 using magnetic resonance imaging and PBS. GV1001 increased the survival of 3xTg-AD mice. It decreased BACE and Aß1-42 levels, neurodegeneration (i.e., reduced CA1, CA3 and dentate gyrus volume, decreased levels of senescence-associated ß-galactosidase positive cells, and increased telomere length and telomerase activity), and levels of ageing-associated proteins. We suggest that GV1001 exerts anti-ageing effects in 3xTg-AD mice by reducing neurodegeneration and senescence, which contributes to improved survival.

Low-temperature-grown InGaAs terahertz photomixer embedded in InP thermal spreading layer regrown by metalorganic chemical vapor deposition.

A novel buried photomixer for integrated photonic terahertz devices is proposed. The active region of the mesa-structure InGaAs photomixer is buried in an InP layer grown by metalorganic chemical vapor deposition (MOCVD) to improve heat dissipation, which is an important problem for terahertz photomixers. The proposed photomixer shows good thermal properties compared to a conventional planar-type photomixer. The MOCVD regrowth process indicates the possibility for THz photomixers to be integrated monolithically with conventional photonic devices.

Design of Novel Tricaprylin-Incorporated Multi-Layered Liposomal System for Skin Delivery of Ascorbic Acid with Improved Chemical Stability.

L-ascorbic acid (Vit C) possesses a variety of dermatological functions in maintaining skin health and anti-aging properties. However, its topical application is challenging owing to its liability to light, oxygen, or heat. Therefore, in this study, a novel liposomal system, including a lipophilic neutral oil named a lipo-oil-some (LOS), was designed to improve the chemical stability and aid the skin absorption of Vit C. The vesicular systems were prepared using the ethanol injection method, employing phosphatidylcholine, cholesterol, dipalmitoyl-sn-glycerol-3-phosphoglycerol, and tricaprylin as neutral oil. The optimized LOS was characterized as follows: shape, multi-layered sphere; size, 981 nm; zeta potential, -58 mV; and Vit C encapsulation efficiency, 35%. The encapsulation of the labile compound into the novel system markedly enhanced photostability, providing over 10% higher Vit C remaining compared to Vit C solution or Vit C-loaded conventional liposome under a light intensity of 20,000 lx. On the other hand, the ex vivo skin permeation and accumulation of Vit C with the LOS system were comparable to those of smaller conventional liposomes (198 nm) in a Franz diffusion cell model mounted with porcine skin. Based on these findings, we concluded that the novel liposomal system could be utilized for skin delivery of Vit C with enhanced chemical stability.

Arterial spin labeling signal ratio between the lesion and contralateral sides for evaluation of acute middle cerebral artery infarct.

ABSTRACT: The purpose of our study was to differentiate arterial transit artifact from post-recanalization luxury perfusion on arterial spin labeling (ASL) image, and obtain the relationship between ASL signal intensity and clinical outcomes in patients with acute ischemic stroke.Thirty-five subjects with an acute middle cerebral artery (MCA) infarct were enrolled (18 with recanalized and 17 with non-recanalized MCAs). ASL images were obtained using pseudo-continuous ASL technique with 1600 ms (millisecond) of post-label delay within 3 days from symptom onset. Signal intensities on color ASL images were classified as high, intermediate, and poor grade visually. The ratio of maximum ASL signal between the ischemic area and contralateral side was calculated and compared between patients with and without MCA recanalization. Among patients with non-recanalized MCA, ASL signal ratios were compared between patients with and without hyperintense vessel sign on fluid attenuated inversion recovery (FLAIR). Also, correlation between the ASL signal ratio and National Institutes of Health Stroke Scale (NIHSS) score was evaluated.High or intermediate grade on color ASL images were more frequently found in patients with recanalized MCA (P < .01). Patients with non-recanalized MCA had higher ASL signal ratio in overall ASL signal grade (P = .010) and intermediate grade (P = .011). Among patients with non-recanalized MCA, those with hyperintense vessel sign on FLAIR had higher ASL signal ratios (P = .049). ASL signal ratio was negatively correlated with both initial (P = .023) and final (P = .003) NIHSS scores.The ASL signal ratio could help to differentiate between the pial collaterals and post-recanalization luxury perfusion. A higher ASL ratio was related with the hyperintense vessel sign on FLAIR and lower NIHSS score.

Brain activation in response to visual sexual stimuli in male patients with right middle cerebral artery infarction: The first case-control functional magnetic resonance imaging study.

ABSTRACT: Sexual dysfunction is a common problem after cerebral infarction; however, little is known about sexual arousal in poststroke patients. Thus, this study aimed to investigate brain activation in response to visual sexual stimuli in patients with right middle cerebral artery (MCA) territory infarction using functional magnetic resonance imaging (fMRI). Using fMRI in 20 participants (11 right MCA infarction patients and 9 age-matched healthy controls), we assessed brain activation elicited by visual sexual stimuli (erotic images) and visual nonsexual stimuli (landscape images). In right MCA infarction patients, the left dorsolateral prefrontal cortex and the left frontal subgyral area were more strongly activated by visual sexual stimuli than by nonvisual sexual stimuli. Brain areas that were more activated by visual sexual stimuli in right MCA infarction patients than in controls included the right parahippocampal gyrus and the bilateral frontal subgyral area. These fMRI results suggest that brain activation patterns in response to visual sexual stimuli might be influenced by right MCA infarction. Further research is needed to explore the association between sexual dysfunction and brain activation in poststroke patients.

CT texture analysis of tonsil cancer: Discrimination from normal palatine tonsils.

The purposes of the study were to determine whether there are differences in texture analysis parameters between tonsil cancers and normal tonsils, and to correlate texture analysis with 18F-FDG PET/CT to investigate the relationship between texture analysis and metabolic parameters. Sixty-four patients with squamous cell carcinoma of the palatine tonsil were included. A ROI was drawn, including all slices, to involve the entire tumor. The contralateral normal tonsil was used for comparison with the tumors. Texture analysis parameters, mean, standard deviation (SD), entropy, mean positive pixels, skewness, and kurtosis were obtained using commercially available software. Parameters were compared between the tumor and the normal palatine tonsils. Comparisons were also performed among early tonsil cancer, advanced tonsil cancer, and normal tonsils. An ROC curve analysis was performed to assess discrimination of tumor from normal tonsils. Correlation between texture analysis and 18F-FDG PET/CT was performed. Compared to normal tonsils, the tumors showed a significantly lower mean, higher SD, higher entropy, lower skewness, and higher kurtosis on most filters (p<0.001). On comparisons among normal tonsils, early cancers, and advanced tonsil cancers, SD and entropy showed significantly higher values on all filters (p<0.001) between early cancers and normal tonsils. The AUC from the ROC analysis was 0.91, obtained from the entropy. A mild correlation was shown between texture parameters and metabolic parameters. The texture analysis parameters, especially entropy, showed significant differences in contrast-enhanced CT results between tumor and normal tonsils, and between early tonsil cancers and normal tonsils. Texture analysis can be useful as an adjunctive tool for the diagnosis of tonsil cancers.

Montelukast microsuspension with hypromellose for improved stability and oral absorption.

Oral montelukast (MTK) is prescribed to treat asthma or rhinitis, and is clinically investigated as new medication in the treatment of Alzheimer's dementia. Herein, in order to better patient's compliance, microsuspensions (MSs)-based oral liquid preparations of montelukast (MTK) were formulated with polymeric suspending agents including hypromellose (HPMC), and those drug-polymer interaction, physicochemical stability, dissolution, and in vivo pharmacokinetic profile was evaluated. When amorphous MTK particle was suspended in aqueous vehicle, it was readily converted into crystalline form and grown into aggregates, drastically lowering dissolution rate. However, the addition of HPMC polymer markedly suppressed the crystal growth, providing both improved drug stability and profound dissolution profile. Raman spectrometry denoted the inter-molecular hydrogen boding between MTK particle and HPMC polymer. The crystal growth or dissolution profile of MSs was markedly affected by pharmaceutical additives (sucrose or simethicone) in the preparations or storage temperature. The optimized HPMC-based MS exhibited over 80% higher bioavailability, compared to marketed granule (Singulair®) in rats. Therefore, novel MTK-loaded MS can be a promising liquid preparation, bettering oral absorption and patient's compliance.

Microbleeds in the Corpus Callosum in Anoxic Brain Injury.

Purpose: This study was performed to evaluate the relationship between callosal microbleeds and anoxic brain injury. Materials and Methods: Twenty-seven patients with anoxic brain injuries were analyzed and retrospectively compared to the control group of patients without a history of anoxic brain injury using Fisher's exact test regarding comorbidities and cerebral microbleeds. The patient group was subdivided according to the presence of callosal microbleeds. Fisher's exact test was used to compare the presence of typical MRI findings of anoxic brain injury, use of cardiopulmonary resuscitation, and prognosis. The Mann-Whitney U test was used to compare the interval between the occurrence of anoxic brain injury to MRI acquisition. Results: The prevalence of cerebral microbleeds in the patient group was 29.6%, which was significantly higher than that in the control group at 3.7% (p = 0.012). All cerebral microbleeds in the patient group were in the corpus callosum. Compared with the callosal microbleed-absent group, the callosal microbleed-present group showed a tendency of good prognosis (6/8 vs. 11/19), fewer typical MRI findings of anoxic brain injury (2/8 vs. 10/19), and more cardiopulmonary resuscitation (6/8 vs. 12/19), although these differences did not reach statistical significance (p = 0.35, p = 0.19, and p = 0.45, respectively). Conclusion: Callosal microbleeds may be an adjunctive MRI marker for anoxic brain injury.

A novel visual ranking system based on arterial spin labeling perfusion imaging for evaluating perfusion disturbance in patients with ischemic stroke.

We developed a visual ranking system by combining the parenchymal perfusion deficits (PPD) and hyperintense vessel signals (HVS) on arterial spin labeling (ASL) imaging. This study aimed to assess the performance of this ranking system by correlating with subtypes classified based on dynamic susceptibility contrast (DSC) imaging for evaluating the perfusion disturbance observed in patients with ischemic stroke. 32 patients with acute or subacute infarcts detected by DSC imaging were reviewed. Each patient's brain was divided into 12 areas. ASL ranks were defined by the presence (+) or absence (-) of PPD/HVS as follows; I:-/-, II:-/+, III: +/+, and IV: +/-. DSC imaging findings were categorized based on cerebral blood flow (CBF) and time to peak (TTP) as normal (normal CBF/TTP), mismatched (normal CBF/delayed TTP), and matched (decreased CBF/delayed TTP). Two reviewers rated perfusion abnormalities in the total of 384 areas. The four ASL ranks correlated well with the DSC subtypes (Spearman's r = 0.82). The performance of ASL ranking system was excellent as indicated by the area under the curve value of 0.94 using either matched or mismatched DSC subtype as the gold standard and 0.97 using only the matched DSC subtype as the gold standard. The two methods were in good-to-excellent agreement (maximum κ-values, 0.86). Inter-observer agreement was excellent (κ-value, 0.98). Although the number of patients was small and the number of dropouts was high, our proposed, ASL-based visual ranking system represented by PPD and HVS provides good, graded estimates of perfusion disturbance that agree well with those obtained by DSC perfusion imaging.

Respiratory syncytial virus-associated seizures in Korean children, 2011-2016.

PURPOSE: Respiratory syncytial virus (RSV) infection can cause various neurological complications. This study aimed to investigate the RSV-associated neurologic manifestations that present with seizures. METHODS: We retrospectively reviewed the medical records of patients aged less than 15 years with laboratory-confirmed RSV infections and seizures between January 2011 and December 2016 in a regional hospital in South Korea. RESULTS: During this period, 1,193 patients with laboratory-confirmed RSV infection were identified. Of these, 35 (35 of 1,193, 2.93%; boys, 19; girls, 16; mean age: 20.8±16.6 months) presented with seizures. Febrile seizure was the most common diagnosis (27 of 35, 77.1%); simple febrile seizure in 13 patients (13 of 27, 48.1%) and complex febrile seizure in 14 (14 of 27, 51.9%). Afebrile seizures without meningitis or encephalopathy were observed in 5 patients (5 of 35, 14.3%), seizures with meningitis in 2 (2 of 35, 5.7%), and seizure with encephalopathy in 1 (1 of 35, 2.9%) patient. Lower respiratory symptoms were not observed in 8 patients. In a patient with encephalopathy, brain diffusion-weighted magnetic resonance imaging revealed transient changes in white matter, suggesting cytotoxic edema as the mechanism underlying encephalopathy. Most patients recovered with general management, and progression to epilepsy was noted in only 1 patient. CONCLUSION: Although febrile seizure is the most common type of seizure associated with RSV infection, the proportion of patients with complex febrile seizure was higher than that of general febrile seizure. Transient cytotoxic edema may be a pathogenic mechanism in RSV-related encephalopathy with seizures.

Glia-Like Cells from Late-Passage Human MSCs Protect Against Ischemic Stroke Through IGFBP-4.

Stem cell therapy is considered to be a promising future treatment for intractable neurological diseases, although all the clinical trials using stem cells have not yet shown any good results. Early passage mesenchymal stem cells (MSCs) have been used in most clinical trials because of the issues on safety and efficacy. However, it is not easy to get plenty of cells enough for the treatment and it costs too much. Lots of late passage MSCs can be obtained at lower cost but their efficacy would be a big hurdle for clinical trials. If late passage MSCs with better efficacy could be used in clinical trials, it could be a new and revolutionary solution to reduce cost and enhance easier clinical trials. In the present study, it was investigated whether late passage MSCs could be induced into glia-like cells (ghMSCs); ghMSCs had better efficacy and they protected neurons and the brain from ischemia, and insulin-like growth factor binding protein-4 (IGFBP-4) played a critical role in beneficial effect of ghMSCs. ghMSCs were induced from MSCs and treated in in vitro and in vivo models of ischemia. They effectively protected neurons from ischemia and restored the brain damaged by cerebral infarction. These beneficial effects were significantly blocked by IGFBP-4 antibody. The current study demontsrated that late passage hMSCs can be efficiently induced into ghMSCs with better neuroprotective effect on ischemic stroke. Moreover, the results indicate that IGFBP-4 released from ghMSCs may serve as one of the key neuronal survival factors secreted from ghMSCs.