Effects of urethane on the response properties of visual cortical neurons in young adult and old cats

Previous studies have shown that visual cortical neurons in old mammals exhibit higher spontaneous activity,higher responsiveness to visual stimuli,and lower selectivity for stimulus orientations and motion directions than did neurons in young adult counterparts.However,whether the responsive difference in cortical neurons between young and old animals resulted from different effects induced by anesthetics has remained unclear.To clarify this issue,we recorded the response properties of individual neurons in the primary visual cortex of old and young adult cats while systematically varying the anesthesia level of urethane,a widely used anesthetic in physiology experiments.Our results showed that cumulatively administrating 50 mg and 100 mg of urethane upon the minimal level of urethane required to anesthetize an old or young adult cat did not significantly alter the degree of neuronal response selectivity for stimulus orientations and motion directions nor significantly change the visually-driven response and spontaneous activity of neurons in old and young adult cats.Cumulatively administrating 150 mg of urethane decreased neuronal responsiveness similarly in both age groups.Therefore,urethane appears to exert similar effects on neuronal response properties of old and young adult animals.

The Assessment of the Clinical Effect of the Drug Compatibility and Course of Treatment to the Brucellar Spondylitis

Objective: To evaluate five drug treatment regimens in the treatment of Brucella spondylitis. Methods: Patients with clinical symptoms compatible and diagnostic test consistent with Brucella spondylitis were randomly assigned to five drug treatment regimens. Results: Combination therapy with doxycycline, rifampin and sulfamethoxazole for 56 consecutive days showed the highest cure rate of 20% after a single course and of 85% after a double course with affectivity rates of 55% and 95%. Cure rate and affectivity rate was significant better (P 0.05) than for patients receiving doxycycline, rifampin and streptomycin for the same period and regimens containing doxycycline were significant better than regimens without this drug. Conclusion: Combination therapy of doxycycline, rifampin and sulfamethoxazole for 8 weeks using one or two full courses should be recommended for Brucella spondylitis.

Risk Factors Affecting Ischemic Stroke: A Potential Side Effect of Antihypertensive Drugs

Background: Stroke is a worldwide health problem, the world’s second-leading cause of death and third-leading cause of disability. Currently, the majority of stroke patients are ischemic stroke patients. It is necessary to evaluate risk factors to prevent ischemic stroke. Data and Methods: The risk factors for stroke in the previous fiscal year were analyzed. They were divided into nonmodifiable and modifiable factors. The probit and ordered probit models were used in the study, with 59341 and 50542 observations used in the estimation of the models, respectively. Results: Among the nonmodifiable factors, age, gender and cerebrovascular disease history are important risk factors. The history of cerebrovascular diseases is considered to be an especially important factor. Among the modifiable factors, taking antihypertensive drugs and recent large weight change are negative risk factors;however, sleeping well significantly reduces the probability of ischemic stroke. Conclusion: It is very important to ensure that medical personnel know a patient’s history of cerebrovascular diseases for proper treatments. Ischemic stroke might be considered an important side effect of antihypertensive drugs. Limitations: The dataset was observatory. There are various types of antihypertension drugs, and their effects are not analyzed.

The brain-derived neurotrophic factor in neuronal plasticity and neuroregeneration: new pharmacological concepts for old and new drugs

Neurotrophins：Neurotrophins are peptides or proteins that are known to regulate neuronal viability,development,and function Beyond synaptic plasticity,neurotrophins protect neurons from apoptosis and also promote neurogenesis to recover neuronal defici even in adulthood.

The neuroprotective effects of the anti-diabetic drug linagliptin against Aβ-induced neurotoxicity

Impaired insulin signaling in Alzheimer’s disease（AD）brains：The insulin signaling pathway is a fundamental physiological mechanism that presents in nearly all vertebrate cells.However,sometimes cells stop responding properly to insulin stimulation.This condition is known as insulin resistance,which is a hallmark of two very common conditions,metabolic syndrome and type 2 diabetes（T2D）.

Excellent effects and possible mechanisms of action of a new antibody–drug conjugate against EGFR-positive triple-negative breast cancer

Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast cancers.TNBC is characterized by its highly metastatic and recurrent features,as well as a lack of specific targets and targeted therapeutics.Epidermal growth factor receptor(EGFR)is highly expressed in a variety of tumors,especially in TNBC.LR004-VC-MMAE is a new EGFR-targeting antibody–drug conjugate produced by our laboratory.This study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor action.Methods:LR004-VC-MMAE was prepared by coupling a cytotoxic payload(MMAE)to an anti-EGFR antibody(LR004)via a linker,and the drug-to-antibody ratio(DAR)was analyzed by HIC-HPLC.The gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset(GSE41313)and Western blotting.MDA-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE(0,0.0066,0.066,0.66,6.6 nmol/L),and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony formation.The migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VCMMAE concentrations(2.5 and 5 nmol/L)with wound healing and Transwell invasion assays.Flow cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells(MDA-MB-468 and MDA-MB-231 cells).The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in vivo.Briefly,BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDAMB-231 cells.Then they were randomly divided into 4 groups(n=6 per group)and treated with PBS,naked LR004(10 mg/kg),LR004-VC-MMAE(10 mg/kg),or doxorubicin,respectively.Tumor sizes and the body weights of mice were measured every 4 d.The effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed by flow cytometry.Western blotting was used to detect the effects of LR004-VC-MMAE on EGFR,ERK,MEK phosphorylation and tumor stemness marker gene expression.Results:LR004-VC-MMAE with a DAR of 4.02 were obtained.The expression of EGFR was found to be significantly higher in TNBC cells compared with non-TNBC cells(P<0.01).LR004-VC-MMAE inhibited the proliferation of EGFRpositive TNBC cells,and the ICvalues of MDA-MB-468 and MDA-MB-231 cells treated with LR004-VC-MMAE for 72 h were(0.13±0.02)nmol/L and(0.66±0.06)nmol/L,respectively,which were significantly lower than that of cells treated with MMAE[(3.20±0.60)nmol/L,P<0.01,and(6.60±0.50)nmol/L,P<0.001].LR004-VC-MMAE effectively inhibited migration and invasion of MDA-MB-468 and MDA-MB-231 cells.Moreover,LR004-VC-MMAE also killed tumor stem cells in EGFR-positive TNBC cells and impaired their tumorsphere-forming ability.In TNBC xenograft models,LR004-VC-MMAE at 10 mg/kg significantly suppressed tumor growth and achieved complete tumor regression on day 36.Surprisingly,tumor recurrence was not observed until the end of the experiment on day 52.In a mechanistic study,we found that LR004-VC-MMAE significantly induced cell apoptosis and cell cycle arrest at G/M phase in MDAMB-468[(34±5)%vs.(12±2)%,P<0.001]and MDA-MB-231[(27±4)%vs.(18±3)%,P<0.01]cells.LR004-VC-MMAE also inhibited the activation of EGFR signaling and the expression of cancer stemness marker genes such as Oct4,Sox2,KLF4 and EpCAM.Conclusions:LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes.It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC.

Study on Anti-diarrhea Effect of the Prescription of 4 Tibetan Veterinary Drugs

This study was conducted to investigate the effects of extracts of 4 Tibetan veterinary drugs on bacterial diarrhea, and to guide the clinical treatment of the disease. The inhibitory effects of the extracts of the 4 Tibetan veterinary drugs, Veronica ciliate Fisch, Usnea diffracta Vain, Sophoraflavescens var. flavescens, Lamiophlomis rotata （ Benth. ） Kudo on 14 common diarrheagenic bacteria were detected by K-B diffusion method and micro-broth dilution method. Optimization was performed on prescriptions of the 4 Tibetan veterinary drugs using orthogonal design software, and a mouse bacterial diarrhea model was established with a clinical isolate, Salmonella blegdam. According to the LD50 value of the optimal prescription of the 4 Tibetan veterinary drugs, the established mouse bacterial diarrhea model was treated in 3 dose groups, i. e. , the high, middle and low dose groups （0. 060, 0. 030 and 0. 020 g/ml, respectively）. The results showed that the 4 Tibetan veterinary drugs had very good inhibitory effects on most of the tested diarrheagenic bacteria, and among them, U. diffracta had better inhibitory effects on all the tested bacteria. The optimal prescription of the d Tibetan veterinary drugs （high dose, 0.06 g/ml） exhibited very good inhibitory effect on mouse diarrhea, indicating that the prescription has very good anti-diarrhea effect, which is beneficial to the clinical treatment of such disease and the development of Tibetan veterinary drugs.

Medical plant extracts and natural compounds with a hepatoprotective effect against damage caused by antitubercular drugs: A review

Drug-induced liver injury encompasses a spectrum of diseases ranging from mild biochemical abnormalities to acute liver failure; example of this scenery is hepatotoxicity caused by the first-line antituberculous drugs isoniazid, rifampin and pyrazinamide, which are basic for treatment of drug-sensible and drug-resistant tuberculosis. In the search for pharmacological alternatives to prevent liver damage, antitubercular drugs have been the subject of numerous studies and published reviews, a great majority of them carried out by Asian countries. At the same time, hepatoprotectors from plant source are now emerging as a possible alternative to counteract the toxic effects of these therapeutic agents. The present review aims to highlight the most recent studies on the subject, based information published in scientific databases such as Scopus and Pub Med.

Effects of fractal gating of potassium channels on neuronal behaviours

The classical model of voltage-gated ion channels assumes that according to a Markov process ion channels switch among a small number of states without memory, but a bunch of experimental papers show that some ion channels exhibit significant memory effects, and this memory effects can take the form of kinetic rate constant that is fractal. Obviously the gating character of ion channels will affect generation and propagation of action potentials, furthermore, affect generation, coding and propagation of neural information. However, there is little previous research on this series of interesting issues. This paper investigates effects of fractal gating of potassium channel subunits switching from closed state to open state on neuronal behaviours. The obtained results show that fractal gating of potassium channel subunits switching from closed state to open state has important effects on neuronal behaviours, increases excitability, rest potential and spiking frequency of the neuronal membrane, and decreases threshold voltage and threshold injected current of the neuronal membrane. So fractal gating of potassium channel subunits switching from closed state to open state can improve the sensitivity of the neuronal membrane, and enlarge the encoded strength of neural information.

Chromatographic behavior of co-eluted plasma compounds and effect on screening of drugs by APCI-LC-MS(/MS):Applications to selected cardiovascular drugs

Chromatographic behavior of co-eluted compounds from un-extracted drug-free plasma samples was studied by LC-MS and LC-MS/MS with positive APCI.Under soft gradient,total ion chromatogram（TIC） consisted of two major peaks separated by a constant lower intensity region.Early peak（0.15-0.4 min） belongs to polar plasma compounds and consisted of smaller mass ions（m/z〈 250）;late peak（3.6-4.6 min） belongs to thermally unstable phospholipids and consisted of fragments with mlz〈300.Late peak is more sensitive to variations in chromatographic and MS parameters.Screening of most targeted cardiovascular drugs at levels lower than 50 ng/mL has been possible by LC-MS for drugs with retention factors larger than three.Matrix effects and recovery,at 20 and 200 ng/mL,were evaluated for spiked plasma samples with 15 cardiovascular drugs,by MRM-LC-MS/MS.Average recoveries were above 90%and matrix effects expressed as percent matrix factor（%MF） were above 100%,indicating enhancement character for APCI.Large uncertainties were significant for drugs with smaller masses（m/z〈 250） and retention factors lower than two.

Protective Effect of Interleukin-1β on Motor Neurons after Sciatic Nerve Injury in Rats

Protective effect of interleukin 1β (IL 1β) on motor neurons was studied after peripheral nerve injury. Twenty Wistar rats were divided into 2 groups randomly. The right sciatic nerve of each rat was resected. After silicon tubulization of sciatic nerve in rat, 15 μl 1 ng/ml IL 1β and PBS solution were injected into the silicon capsule respectively. Enzyme histochemistry was performed to show acetyle cholesterase (AchE) and nitric oxide staining (NOS) activity of spinal α motor neurons in spinal segments 2 weeks later. Neurons were counted and the diameter and cross sectional (c/s) area of neurons were analyzed by using computer image analysis system. The results showed that as compared with the normal side, both enzyme activities significantly changed in motor neurons in PBS group. The diameter and c/s area of both neurons changed significantly too ( P< 0 01). These results suggest that exogenous IL 1β protects α motor neurons from degeneration and necrosis after peripheral nerve injury.

Three-dimensional aspects of formulation excipients in drug discovery:a critical assessment on orphan excipients,matrix effects and drug interactions

Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.

Vitamin D,selenium,and antidiabetic drugs in the treatment of type 2 diabetes mellitus with Hashimoto's thyroiditis

BACKGROUND Diabetes and thyroiditis are closely related.They occur in combination and cause significant damage to the body.There is no clear treatment for type-2 diabetes mellitus(T2DM)with Hashimoto's thyroiditis(HT).While single symptomatic drug treatment of the two diseases is less effective,combined drug treatment may improve efficacy.AIM To investigate the effect of a combination of vitamin D,selenium,and hypoglycemic agents in T2DM with HT.METHODS This retrospective study included 150 patients with T2DM and HT treated at The Central Hospital of Shaoyang from March 2020 to February 2023.Fifty patients were assigned to the control group,test group A,and test group B according to different treatment methods.The control group received low-iodine diet guidance and hypoglycemic drug treatment.Test group A received the control treatment plus vitamin D treatment.Test group B received the group A treatment plus selenium.Blood levels of markers of thyroid function[free T3(FT3),thyroid stimulating hormone(TSH),free T4(FT4)],autoantibodies[thyroid peroxidase antibody(TPOAB)and thyroid globulin antibody(TGAB)],blood lipid index[low-density lipoprotein cholesterol(LDL-C),total cholesterol(TC),triacylglycerol(TG)],blood glucose index[fasting blood glucose(FBG),and hemoglobin A1c(HbA1c)]were measured pre-treatment and 3 and 6 months after treatment.The relationships between serum 25-hydroxyvitamin D3[25(OH)D3]level and each of these indices were analyzed.RESULTS The levels of 25(OH)D3,FT3,FT4,and LDL-C increased in the order of the control group,test group A,and test group B(all P<0.05).The TPOAB,TGAB,TC,TG,FBG,HbA1c,and TSH levels increased in the order of test groups B,A,and the control group(all P<0.05).All the above indices were compared after 3 and 6 months of treatment.Pre-treatment,there was no divergence in serum 25(OH)D3 level,thyroid function-related indexes,autoantibodies level,blood glucose,and blood lipid index between the control group,test groups A and B(all P>0.05).The 25(OH)D3 levels in test groups A and B were negatively correlated with FT4 and TGAB(all P<0.05).CONCLUSION The combination drug treatment for T2DM with HT significantly improved thyroid function,autoantibody,and blood glucose and lipid levels.

Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes

There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system(RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials(RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios(HR) regarding the treatment effects of these drugs for cardiovascular disease(CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.

Death as a Drug Side Effect in FAERS: Is Glyphosate Contamination a Factor?

An analysis of selected datasets from the FDA’s drug Adverse Event Reporting System (FAERS) leads us to hypothesize that glyphosate contamination in both food and drugs is a major contributor to chronic and acute kidney failure respectively. In chronic kidney failure, glyphosate-induced pancreatitis results in the release of trypsin, causing a leaky vasculature. The albumin-bound glyphosate escapes into the tissues, protecting the circulatory system and kidneys but resulting in multiple symptoms related to skin, gut, brain, bones, lungs, etc. The rare and poorly understood acute kidney failure response reported for protamine sulfate and Trasylol? is strikingly similar to that associated with glyphosate poisoning. Both drugs are derived from biological tissues that are plausibly contaminated with glyphosate. These drugs protect from haemorrhage, which leads to retention of glyphosate in the vasculature, are followed by circulatory collapse and a high likelihood of death as an outcome. We support our argument by comparing symptom profiles of selected subsets of FAERS with those related to glyphosate poisoning, anomalous reactions to protamine sulfate, and conditions showing strong statistical time-trend correlations with glyphosate.

Preventive Effects of Five Drugs on Mycoplasma Pneumonia of Swine (MPS)

The paper was to explore the preventive effects of five drugs on mycoplasma pneumonia of swine （MPS） and to provide reference for clinical medication of pig farms in Hainan Province. A total of 444 health piglets were randomly divided into 6 groups, including five medication groups （72 piglets in group A, 74 pig- lets in group B, 72 piglets in group C, 76 piglets in group D, 76 piglets in group E） and one control group （74 piglets）. The piglets in experimental groups were treated drugs once a day for successive 5 days at 30, 60, 90, 120 and 150 of age. The piglets in control group were free of medication. At 70 and 140 days of age, 15 piglets of each group were randomly selected to collect their blood sermn. The Mycoplasma hyopneumoniae （M-Hyo） antibodies in serum were measured by en- zyme-linked immunosorbent assay （ELISA）. During the experiment, the incidence rates of respiratory disease, lung lesion, feed conversion rate, average daily gain （ADG）, and mortality rate of pigs were also observed and recorded. The results showed that the five drugs had significant difference in preventative effects. Group C （Zhiyuanjing group） received the best preventive effect and the highest economic benefits. Compared with control group, the ADG and feed conversion rate in group C were increased by 7.53% and 9.09%, respectively; the incidence rate of respiratory disease was reduced by 13.44% and lung lesion was alleviated by 81.43% ; and the earnings of each pig could rise by 132.70 yuan. The preventative effect and economic benefit of the drugs was sequenced by Chansu Kechuanling and Bingchan Kechuanwang. Wante Feilin and amoxicillin had weaker preventive effects against MPS but greatly influenced growth performance of pigs, so they should be used alternatively with other drugs.

Inhibitory effect induced by fractional Gaussian noise in neuronal system

We discover a phenomenon of inhibition effect induced by fractional Gaussian noise in a neuronal system. Firstly,essential properties of fractional Brownian motion(fBm) and generation of fractional Gaussian noise(fGn) are presented,and representative sample paths of fBm and corresponding spectral density of fGn are discussed at different Hurst indexes.Next, we consider the effect of fGn on neuronal firing, and observe that neuronal firing decreases first and then increases with increasing noise intensity and Hurst index of fGn by studying the time series evolution. To further quantify the inhibitory effect of fGn, by introducing the average discharge rate, we investigate the effects of noise and external current on neuronal firing, and find the occurrence of inhibitory effect about noise intensity and Hurst index of f Gn at a certain level of current. Moreover, the inhibition effect is not easy to occur when the noise intensity and Hurst index are too large or too small. In view of opposite action mechanism compared with stochastic resonance, this suppression phenomenon is called inverse stochastic resonance(ISR). Finally, the inhibitory effect induced by fGn is further verified based on the inter-spike intervals(ISIs) in the neuronal system. Our work lays a solid foundation for future study of non-Gaussian-type noise on neuronal systems.

Effect of Homoeopathic Drugs to Control Growth and Production of <i>A. flavus</i>

Five common homoeopathic drugs viz., Belladonna, Bryonia, Colchicum, Colocynth and Lathyrus sat were selected and tested against growth and aflatoxin production of Aspergillus flavus. The result indicates that all five drugs suppressed the growth of A. flavus. The lower concentration of all the tested drugs induced maximum growth of fungi and maximum production of aflatoxin. However, the growth as well as aflatoxin production potentiality was considerably decreased when the concentration of the drug was increased. Out of all the five drugs, Bryonia was comparatively less effective with respect to inhibition in aflatoxin production. But Belladonna was found to be most effective drug on growth and aflatoxin production.

URB597 exerts neuroprotective effect against transient cerebral ischemic injury via restor⁃ing autophagy flux and inhibiting neuronal necroptosis in mice

OBJECTIVE URB597(KDS-4103)is a potent and selective inhibitor of the enzyme fatty acid amide hydrolase(FAAH)and can ele⁃vate the level of oleoylethanolamide(OEA),a naturally occurring endocannabinoid in the brain.However,the effect of URB597 on cerebral isch⁃emic injury in mice remains unclear.METHODS Focal cerebral ischemia was induced by middle cerebral artery occlusion for 30 min followed by reperfusion for 24 h in mice.To observe the dose-dependent effect,URB597(0.04-5.00 mg·kg-1,ip)was administered at the same time of reperfu⁃sion.To determine the time-dependent effect,URB597(1.00 mg·kg-1,ip)was administered as a single dose at 0,1,3 or 5 h after reperfusion.Twenty-four hours after brain ischemia,Beder⁃son scoring test and grip strength test were used to evaluate the neurological function;brain in⁃farct volume was assayed by 2,3,5-triphenyltetra⁃zolium chloride(TTC)staining or diffusion-weighted magnetic resonance imaging(MRI).Laser speckle imaging(LSI)technique was used to assay the regional cerebral blood flow(rCBF);NeuN immunofluorescence staining was used to observe the neuron survival in the penumbra.To further investigate the underlying mechanism,au⁃tophagy flux related proteins(LC3-Ⅱ,P62 and LAMP2)and necroptosis related proteins(pRIPK3 and pMLKL)were detected by Western blotting and immunofluorescence staining.RESULTS Twenty-four hours after brain ischemia,URB597 dose-dependently improved neurological func⁃tion and reduced brain infarct volume.The most effective dose was 1.00 mg·kg-1;the therapeutic time window was within 1 h after ischemic stroke.The protective effect is further confirmed by the results that post-ischemic treatment with URB597(1.00 mg·kg-1)significantly increased neurons survival,promoted autophagy flux and reduced cell necroptosis in cortical penumbra after cerebral I/R.CONCLUSION URB597 dose-and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury.This neu⁃roprotective effect of URB597 may be associated with its restoration of autophagy flux and inhibi⁃tion of neuronal necroptosis in the cortical penumbra.

Neurogenesis-enhancing effect of sodium ferulate and its role in repair following stress-induced neuronal damage

Ferulic acid (FA) is a ubiquitous phenolic acid of low toxicity, and sodium ferulate (SF) is its sodium salt. Our previous studies have revealed that FA shows neuroprotective effect and significant antidepressant- like effect. The aim of this study was to investigate its potential neurogenesis-enhancing effect and its role in repair following stress-induced neuronal damage. MTT assay was performed to measure the effect of SF on the growth of rat pheochromocytoma (PC12) cells;morphological and immunocytochemical meth- ods were used for assessing its differentiation-induc- ing action. Chronic mild stress (CMS) tests were per- formed to establish rat model of depression. The histopathology of animal brains was studied to ana- lyze CMS-induced morphological changes and the effect of SF on the repair of CMS-induced brain in- jury. The expressions of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and the proliferation of neural stem cell/neural progenitor cells were assessed in the hippocampi of chronic mild stress (CMS)-induced depression-like model rats by immunohistochemistry and bromodeoxyuridine (BrdU)- incorporation assays, respectively. Our in vitro tests showed that SF promoted the proliferation of PC12 cells in the concentration range of 5 - 320 μM, and induced PC12 cells to differentiate to more mature cells with the morphological characteristics and mo- lecular marker of neuronal-like cells. In vivo tests showed that SF up-regulated the expressions of NGF and BDNF, and induced the proliferation of neural stem cell/neural progenitor cells in the hippocampi of CMS-induced depression-like model rats. This study provides evidences that SF shows neurogenesis-en- hancing effect, and its antidepressant-like effect of SF may be related directly and closely to its above-men- tioned effect.