Exploring the Global Landscape of Self-Medication Among Students: Trends, Risks, and Recommendations for Safe and Responsible Practices

Objective: This study aimed to provide a comprehensive overview of self-medication practices among students by conducting a bibliometric analysis of the available scientific literature. This research highlights the importance of promoting safe and responsible healthcare behaviors among students. Methods: A systematic search was conducted in the Scopus database to retrieve all peer-reviewed English articles and reviews published from 1968 onwards. The retrieved documents were analyzed to identify publication trends, citation counts, top journals, geographical distribution, and emerging research themes. Results: The findings indicate a significant increase in published literature about student self-medication over the past fifteen years. However, it was observed that the citation count for these documents was lower than expected, suggesting a need for increased attention toward this critical topic. The analysis also identified several hot topics in student self-medication, including the misuse of over-the-counter medications, dietary supplements, and psychoactive substances. The inappropriate use of antibiotics and the self-medication of mental health issues, such as anxiety and depression, were also identified as significant problems. Conclusions and recommendations: Self-medication among students is a complex and critical issue that requires immediate attention. This study highlights the urgent need for greater awareness and education regarding responsible self-medication practices among students. New policies, interventions, and strategies should be developed to address malpractices, misconceptions, and harmful practices related to self-medication. Educational institutions and health authorities should play a crucial role in providing students with mental health resources and support services... (AU)

Clinical Phenotypes of PCOS: a Cross-Sectional Study.

This cross-sectional study examines the Doi-Alshoumer PCOS clinical phenotype classification in relation to measured clinical and biochemical characteristics of women with polycystic ovary syndrome (PCOS). Two cohorts of women (Kuwait and Rotterdam) diagnosed with PCOS (FAI > 4.5%) were examined. These phenotypes were created using neuroendocrine dysfunction (IRMA LH/FSH ratio > 1 or LH > 6 IU/L) and menstrual cycle status (oligo/amenorrhea) to create three phenotypes: (A) neuroendocrine dysfunction and oligo/amenorrhea, (B) without neuroendocrine dysfunction but with oligo/amenorrhea, and (C) without neuroendocrine dysfunction and with regular cycles. These phenotypes were compared in terms of hormonal, biochemical, and anthropometric measures. The three suggested phenotypes (A, B, and C) were shown to be sufficiently distinct in terms of hormonal, biochemical, and anthropometric measures. Patients who were classified as phenotype A had neuroendocrine dysfunction, excess LH (and LH/FSH ratio), irregular cycles, excess A4, infertility, excess T, highest FAI and E2, and excess 17αOHPG when compared to the other phenotypes. Patients classified as phenotype B had irregular cycles, no neuroendocrine dysfunction, obesity, acanthosis nigricans, and insulin resistance. Lastly, patients classified as phenotype C had regular cycles, acne, hirsutism, excess P4, and the highest P4 to E2 molar ratio. The differences across phenotypes suggested distinct phenotypic expression of this syndrome, and the biochemical and clinical correlates of each phenotype are likely to be useful in the management of women with PCOS. These phenotypic criteria are distinct from criteria used for diagnosis.

Functional outcomes of COVID-19 patients with acute ischemic stroke: A prospective, observational, single-center study in North Jordan.

We assessed whether stroke severity, functional outcome, and mortality in patients with ischemic stroke differed between patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and those without. We conducted a prospective, single-center cohort study in Irbid, North Jordan. All patients diagnosed with ischemic stroke and SARS-CoV-2 infection were consecutively recruited from October 15, 2020, to October 16, 2021. We recorded demographic data, vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score, stroke subtype according to the Trial of ORG 10172 in Acute Stroke Treatment Criteria (TOAST), treatments at admission, and laboratory variables for all patients. The primary endpoint was the functional outcome at 3 months assessed using the modified Rankin Score. Secondary outcomes involved in-hospital mortality and mortality at 3 months. We included 178 patients with a mean (standard deviation) age of 67.3 (12), and more than half of the cases were males (96/178; 53.9%). Thirty-six cases were coronavirus disease 2019 (COVID-19) related and had a mean (standard deviation) age of 70 (11.5). When compared with COVID-19-negative patients, COVID-19-positive patients were more likely to have a higher median NIHSS score at baseline (6 vs 11; P = .043), after 72 hours (6 vs 12; P = .006), and at discharge (4 vs 16; P < .001). They were also more likely to have a higher median modified Rankin Score after 3 months of follow-up (P < .001). NIHSS score at admission (odds ratio = 1.387, 95% confidence interval = 1.238-1.553]; P < .001) predicted having an unfavorable outcome after 3 months. On the other hand, having a concomitant SARS-CoV-2 infection did not significantly impact the likelihood of unfavorable outcomes (odds ratio = 1.098, 95% confidence interval = 0.270-4.473; P = .896). The finding conclude that SARS-CoV-2 infection led to an increase in both stroke severity and in-hospital mortality but had no significant impact on the likelihood of developing unfavorable outcomes.

Preclinical and Clinical Applications of Metabolomics and Proteomics in Glioblastoma Research.

Glioblastoma (GB) is a primary malignancy of the central nervous system that is classified by the WHO as a grade IV astrocytoma. Despite decades of research, several aspects about the biology of GB are still unclear. Its pathogenesis and resistance mechanisms are poorly understood, and methods to optimize patient diagnosis and prognosis remain a bottle neck owing to the heterogeneity of the malignancy. The field of omics has recently gained traction, as it can aid in understanding the dynamic spatiotemporal regulatory network of enzymes and metabolites that allows cancer cells to adjust to their surroundings to promote tumor development. In combination with other omics techniques, proteomic and metabolomic investigations, which are a potent means for examining a variety of metabolic enzymes as well as intermediate metabolites, might offer crucial information in this area. Therefore, this review intends to stress the major contribution these tools have made in GB clinical and preclinical research and highlights the crucial impacts made by the integrative "omics" approach in reducing some of the therapeutic challenges associated with GB research and treatment. Thus, our study can purvey the use of these powerful tools in research by serving as a hub that particularly summarizes studies employing metabolomics and proteomics in the realm of GB diagnosis, treatment, and prognosis.

Problematic Use of Social Media Platforms and Its Association With Depression in Pharmacy Students.

Objectives. The objective of this investigation is to examine the association between depression and problematic use of social media among university students with a focus on the differential effect of studying pharmacy as compared to other disciplines.Methods. A cross sectional study was conducted using an online survey that recruited students from different disciplines at one university. Problematic use of social media was measured using the Bergen Social Media Addiction Scale. Depression was assessed using the patient health questionnaire-9 (PHQ-9).Results. Responses from 105 respondents out of 140 invited were analyzed. The average age of participants was 19.9 years (SD=2.1 years). Forty-seven participants (44.8%) reported depression. Depression was less prevalent in pharmacy students than in students of other disciplines (35.7% vs 62.9%, respectively). Social media addiction score (OR: 1.07; 95% CI: 1.01-1.12) and pharmacy discipline (OR: 0.2; 95%: 0.02-0.66) were identified as independent predictors of depression. The extent of problematic use of social media was similar between pharmacy and non-pharmacy students (49.8 and 52.7, respectively).Conclusion Studying pharmacy may have a differential effect on the association between problematic use of social media and the development of depression among undergraduate university students.

Evaluation of Vulnerability Factors for Developing Stress and Depression due to COVID-19 Spread and its Associated Lockdown.

Background: COVID-19 is a pandemic that has been widespread throughout the world. The disease and the measures employed to contain its spread have a detrimental effect on the mental health of individuals. Countries across the world have applied variable combinations of quarantine and social distancing measures to contain the spread of COVID-19. This project aims at identifying the susceptible groups for the development of depression and stress due to COVID-19-associated containment measures. This evaluation will help in prioritizing efforts to ameliorate the detrimental effects of COVID-19 on psychological health. Methods: A cross-sectional study was conducted through an online survey that included questions on the demographics and COVID-19 experience. The prevalence of depressive symptoms was evaluated using the PHQ-9 survey, whereas stress levels were detected using the perceived stress scale (PSS). Data regarding demographics as well as exposure to COVID-19, working at home and the financial impact of the pandemic were collected. Results: Data were collected from 1541 participants from the MENA region. Depressive symptoms were detected in 54.2% of the participants, and the average stress score was 18.4±0.8. Adjusting for demographics and other variables, younger participants were more likely to report depressive symptoms and higher stress scores. Additionally, younger age, female gender, the coexistence of depressive symptoms, negative effects on monthly income, and ability to do work were found to be independent predictors of higher stress scores. Conclusion: Young individuals are more likely to develop depression symptoms and stress. Thus, there is a need for prompt measures to alleviate COVID-19-associated effects on this group.

Saccharin and naltrexone prevent increased pain sensitivity and impaired long-term memory induced by repetitive neonatal noxious stimulation: role of BDNF and enkephalin.

This study aim to examine the hypothesis that repetitive painful stimuli during infancy will alter pain sensitivity and impair learning and memory during adulthood and that saccharin will prevent this through its analgesic effect. Naltrexone is used to examine if saccharin effect is mediated via the endogenous opioid system. Pain in rat pups was induced via needle pricks of the paws on day 1 of their birth (P0). All treatments/ manipulations started on day 1 and continued for 2 weeks. The radial arm water maze (RAWM) test was used to assess learning and memory. Pain threshold through foot-withdrawal response to a hot plate was also assessed. At the end of behavioral tests, animals were killed, hippocampus was dissected, and hippocampal levels of ß-endorphin, enkephalin, and brain-derived neurotropic factor (BDNF) were assessed using ELISA. Naltrexone and saccharin combined normalized noxious stimulation induced increased pain sensitivity later in life. Furthermore, naltrexone and saccharin together mitigated the deficiency in learning and memory induced by noxious stimulation. Saccharin treatment prevented reduction in hippocampal enkephalin. Additionally, saccharin prevented hippocampal noxious stimulation induced BDNF decrement. Saccharin prevented long-term memory impairment during adulthood induced by repeated neonatal pain via mechanisms that appear to involve BDNF. Interestingly, naltrexone did not antagonize the effects of saccharin, instead naltrexone augmented saccharin effects.

Combined crizotinib and endocrine drugs inhibit proliferation, migration, and colony formation of breast cancer cells via downregulation of MET and estrogen receptor.

Hormone-dependent breast cancer is the most abundant molecular subtype of the disease. Despite the availability of endocrine treatments, the use of these drugs is limited by their serious adverse reactions and development of acquired resistance often mediated by growth factor receptors. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and mediating resistance to targeted therapies. Crizotinib is a small-molecule tyrosine kinase inhibitor of MET. In this study, the anticancer effects of combined crizotinib and endocrine drugs were investigated in breast cancer cells in vitro along with the molecular mechanisms associated with these effects. Results showed that crizotinib inhibited growth of MCF7 and T-47D breast cancer cells in a dose-dependent manner with IC50 values of 2.88 µM and 0.93 µM, respectively. Combined treatment of crizotinib and 4-hydroxytamoxifen resulted in synergistic growth inhibition of MCF7 and T-47D cells with combination index values of 0.39 and 0.8, respectively. The combined treatment significantly suppressed migration and colony formation of MCF7 and T-47D cells. Immunofluorescence showed a significant reduction of the expression of the nuclear protein Ki-67 with the combination of crizotinib and 4-hydroxytamoxifen in both cell lines. Western blotting indicated that the combination treatment reduced the levels of active and total MET, estrogen receptor α (ERα), total and active levels of AKT, ERK, c-SRC, NFĸB p65, GSK-3ß, and the anti-apoptotic BCL-2 protein. Findings from this study suggest a potential role of MET inhibitors in breast cancer treatment as monotherapy or combination with endocrine drugs.

ProBDNF is a Novel Mediator of the Interaction Between MDA-MB- 231 Breast Cancer Cells and Brain Microvascular Endothelial Cells.

AIM: The current work aims to assess the role of proBDNF/BDNF in the interaction between brain microvascular endothelial cells and the MDA-MB-231 breast cancer cell line that has been consistently reported to cause brain metastasis. BACKGROUND: Breast cancer brain metastasis (BM) is a significant health problem with limited therapeutic options. The development of BM is a multistep process that requires constant interaction with brain vasculature and the development of tumor blood supply. The benefits of anti-angiogenic modalities, based on antagonizing vascular endothelial growth factor in breast cancer metastasis, did not prove to be effective. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with a reported angiogenic effect. There is a lack of data regarding the involvement of BDNF in metastatic breast cancer interaction with brain microvascular endothelial cells (HBEC-5i). METHODS: Using an adaptive transfer design, the cross-talk between HBEC-5i and MDAMB- 231 cell was investigated. HBEC-5i were treated with MDA-MB-231-conditioned media, and the involvement of BDNF/proBDNF in the interaction was assessed using both release and inhibitor-based assays in migration and in vitro tube formation assay. RESULTS: MDA-MB-231 and HBEC-5i released total BDNF (250 vs. 80 pg/ml, respectively). MDA-MB-231 conditioned media inhibited the migration of HBEC-5i by more than 80% (p<0.05) and tube formation by 75% (p<0.05). Neutralizing mature BDNF did not alter the MDA-MB-231 induced anti-angiogenic effect, which was completely blunted by antagonizing proBDNF. MDA-MB-231 released proBDNF (131.5 pg/ml), and more than 60% of total BDNF released was in the pro-form. CONCLUSION: proBDNF is a novel mediator of breast cancer-induced anti-angiogenic effect in brain endothelial cells.

An Assessment of Patients Factors Effect on Prescriber Adherence to Ischemic Stroke Secondary Prevention Guidelines.

BACKGROUND: Stroke is the leading cause of long-term disability worldwide. Stroke recurrence is a major health problem with devastating consequences. Adherence to secondary prevention guidelines reduced stroke recurrence. Data regarding prescriptions adherence to secondary prevention guidelines in the Middle East and North Africa is lacking. OBJECTIVES: The aim of this study is to assess the degree of physician adherence to ASA guidelines and the patient specific factors that affect their prescribing patterns in a major teaching hospital in Jordan. METHODS: Ischemic stroke patients referring to King Abdullah University Hospital were approached and offered a description of the study to obtain their informed consent. After getting the informed consent, their prescription at the time of discharge was evaluated for adherence to secondary prevention guidelines and classified into adherent and non-adherent based on a composite score that included each of the guidelines which indicated therapeutic classes. Odds ratio for adherence and their 95%confidence intervals were calculated and adherence to specific therapeutics classes was evaluated. RESULTS: Two hundred and seventy-five patients were included in this evaluation. Less than 50% of the patients received guideline's adherent prescriptions. Patients with hypertension and hyperlipidemia were associated with a lower probability were prescribed a guidelines adherent regimen (OR 0.485, 0.0.225, respectively). ACEI/ARBs combination with thiazides was prescribed to about 11.52% of the patients. CONCLUSION: Adherence to stroke secondary prevention guidelines was suboptimal especially in the antihypertensive prescription component. Further assessments and evaluations are required to improve guidelines adherence.

An evaluation of the ability of thrombospondin-1 to predict stroke outcomes and mortality after ischemic stroke.

INTRODUCTION: Thrombspondin-1 (TSP-1) is a glycoprotein that has a variety of functions including suppression of angiogenesis and regulation of extracellular matrix deposition. These functions are central to the recovery process after stroke. Data regarding the association and predictive value of TSP-1 and stroke outcomes are limited. PATIENTS AND METHODS: Patients with ischemic stroke who referred to King Abdullah University Hospital were evaluated for inclusion. The level of serum TSP-1 on admission was assayed using ELISA. Data regarding comorbid diseases as well as stroke severity at baseline, functional outcome and mortality at 6 months were collected prospectively. Favorable outcome was identified as NIHSS or mRS ≤ 1. RESULTS: Ninety-six patients with an average age of 66.7 years were included. One-third of the patients (32 patients) had favorable outcome on admission. The serum TSP-1 levels in patients with favorable outcome were significantly higher (719.7 vs. 639.9; p = 0.028). Similarly, patients with favorable outcome at 6 months had higher levels of TSP-1 at baseline (714.3 vs. 614.7; p = 0.003). TSP-1 was identified as an independent predictor of favorable outcome at baseline (OR = 0.993, p = 0.038) and after 6 months (OR = 0.99, p = 0.008). CONCLUSION: TSP-1 can predict favorable outcomes with regard to the initial severity and long-term functional outcome.

Phenethyisoquinoline alkaloids from the leaves of Androcymbium palaestinum.

Thirteen compounds were isolated from the methanolic extract of the leaves of Androcymbium palaestinum Baker (Colchicaceae). Of these, three were new, two were new natural products, and eight were known. The new isolated compounds were (+)-1-demethylandrocine (5), (-)-andropalaestine (8), and (+)-2-demethyl-ß-lumicolchicone (10), while the new natural products were (+)-O-methylkreysigine-N-oxide (3) and (+)-O,O-dimethylautumnaline (9). Moreover, two known compounds are reported for the first time from this species, specifically (-)-colchicine (11) and (-)-3-demethyldemecolcine (13). The structures of the isolated compounds were elucidated using a series of spectroscopic and spectrometric techniques, principally HRESIMS, 1D-NMR (1H and 13C NMR) and 2D-NMR (COSY, edited-HSQC, and HMBC). ECD spectroscopy was used for assigning the absolute configurations of compounds 3, 5, and 10. The cytotoxic activities of the isolated compounds were evaluated using the MDA-MB-435 (melanoma), MDA-MB-231 (breast), and OVCAR3 (ovary) cancer cell lines. Compound 11 was the most potent against all tested cell lines, with IC50 values of 12, 95 and 23 nM, respectively.

Effects of the synthetic cannabinoid XLR-11 on the viability and migration rates of human brain microvascular endothelial cells in a clinically-relevant model.

BACKGROUND: Synthetic cannabinoids (SCs) are a group of newly-developed drugs that bind and activate endocannabinoid system receptors. Angiogenesis is a biological process in which new blood vessels are formed from preexistent blood vessels. It plays a vital role in tissue growth, wound healing, and embryogenesis. This study aims to investigate the effects of the synthetic cannabinoid XLR-11 on specific cellular functions such as viability and angiogenesis in vitro. METHODS: Human brain microvascular endothelial cells (HBMECs) were cultured in DMEM/F12 medium supplemented with an endothelial cell growth kit. The MTT assay was used to investigate the viability of endothelial cells. An endothelial cell migration assay was used to investigate migration ability, while a tube formation assay was used to investigate the angiogenic capacity of the endothelial cells. RESULTS: XLR-11 was found to enhance the viability of HBMECs. Moreover, the migration rate and angiogenic capacity significantly increased in the presence of various concentrations of XLR-11 compared to the control. CONCLUSION: The current study shows that XLR-11 increases the viability of human brain microvascular endothelial cells and enhances angiogenesis in the brain in vitro, suggesting that XLR-11 could potentially be used as a therapeutic angiogenic drug in human brain injury treatment.

Glycosylated Hemoglobin A1c Is Associated with Anthropometric Measurements and Tumor Characteristics in Breast Cancer Patients.

PURPOSE: To investigate the association between glycosylated hemoglobin A1c (HbA1c) with anthropometric measurements and clinicopathologic characteristics of breast cancer patients. Such data are lacking in Arabian countries. PATIENTS AND METHODS: A cross-sectional study was conducted at the Outpatient Oncology Unit at King Hussein Medical Center at the Royal Medical Services (RMS) and 223 breast cancer patients were included. Blood levels of HbA1c were measured and patients were classified into normal/non-diabetic (HbA1c <5.7%), prediabetic (HbA1c 5.7-6.4%), and diabetic (HbA1c ≥6.5%). RESULTS: The average age of patients was 49.9±10.3 years. Most patients had waist circumference equal to or more than 80 cm (91.9%) and more than half (55.2%) had waist-hip ratio equal to or more than 0.85. Mean body mass index (BMI) was 29.9±5.7 kg/m2. The mean level of HbA1c was 6.2±1.4% (range 4.7% to 12.6%). HbA1c levels revealed that most patients in this study classified as prediabetics (44.4%). There was a significant positive correlation between HbA1c levels and each of patient's age (r=0.267, p<0.001), waist circumference (r=0.180, p=0.008), and waist-hip ratio (r=0.278, p<0.001). Compared with premenopausal breast cancer patients, postmenopausal patients had significantly higher HbA1c blood levels (t=-3.542, p=0.003). HbA1c was significantly associated with stage (p=0.044) and grade (p=0.016) of carcinoma in premenopausal breast cancer patients. Among postmenopausal cases, HbA1c was significantly associated with molecular subtype of the disease (p=0.039). CONCLUSION: The majority of Jordanian breast cancer patients in this study are prediabetic, obese, and had visceral obesity. HbA1c levels are increased among older patients and those who have greater waist circumference and waist-hip ratio. HbA1c is associated with advanced stage and grade of breast carcinoma in premenopausal patients and with molecular subtype in postmenopausal cases. These findings urge the need to screen breast cancer patients for glycemic status upon disease presentation and to further consider treatments to control hyperglycemia in order to reduce the impact of metabolic derangements on disease prognosis and outcomes.

Silymarin Ameliorates Diabetes-Induced Proangiogenic Response in Brain Endothelial Cells through a GSK-3ß Inhibition-Induced Reduction of VEGF Release.

Diabetes mellitus (DM) is a major risk factor for cardiovascular disease. Additionally, it was found to induce a dysfunctional angiogenic response in the brain that was attributed to oxidative stress. Milk thistle seed extract (silymarin) has potent antioxidant properties, though its potential use in ameliorating diabetes-induced aberrant brain angiogenesis is unknown. Glycogen synthase kinase-3ß is a regulator of angiogenesis that is upregulated by diabetes. Its involvement in diabetes-induced angiogenesis is unknown. To evaluate the potential of silymarin to ameliorate diabetes-induced aberrant angiogenesis, human brain endothelial cells (HBEC-5i) were treated with 50 µg/mL advanced glycation end (AGE) products in the presence or absence of silymarin (50, 100 µM). The angiogenic potential of HBEC-5i was evaluated in terms of migration and in vitro tube formation capacities. The involvement of GSK-3ß was also evaluated. AGE significantly increased the migration and tube formation rates of HBEC-5i by about onefold (p = 0.0001). Silymarin reduced AGE-induced migration in a dose-dependent manner where 50 µM reduced migration by about 50%, whereas the 100 µM completely inhibited AGE-induced migration. Similarly, silymarin 50 µg/mL blunted AGE-induced tube formation (p = 0.001). This effect was mediated through a GSK-3ß-dependent inhibition of VEGF release. In conclusion, silymarin inhibits AGE-induced aberrant angiogenesis in a GSK-3ß-mediated inhibition of VEGF release.

Sucrose and naltrexone prevent increased pain sensitivity and impaired long-term memory induced by repetitive neonatal noxious stimulation: Role of BDNF and ß-endorphin.

Pain in neonates is associated with short and long-term adverse outcomes. Data demonstrated that long-term consequences of untreated pain are linked to the plasticity of the neonate's brain. Sucrose is effective and safe for reducing painful procedures from single events. However, the mechanism of sucrose-induced analgesia is not fully understood. The role of the opioid system in this analgesia using the opioid receptor antagonist Naltrexone was investigated, plus the long-term effects on learning and memory formation during adulthood. Pain was induced in rat pups via needle pricks of the paws. Sucrose solution and/or naltrexone were administered before the pricks. All treatments started on day one of birth and continued for two weeks. At the end of 8weeks, behavioral studies were conducted to test spatial learning and memory using radial arm water maze (RAWM), and pain threshold via foot-withdrawal response to a hot plate. The hippocampus was dissected; levels of brain derived neurotrophic factor (BDNF) and endorphins were assessed using ELISA. Acute repetitive neonatal pain increased pain sensitivity later in life, while naltrexone with sucrose decreased pain sensitivity. Naltrexone and/or sucrose prevented neonatal pain induced impairment of long-term memory, while neonatal pain decreased levels of BDNF in the hippocampus; this decrease was averted by sucrose and naltrexone. Sucrose with naltrexone significantly increased ß-endorphin levels in noxiously stimulated rats. In conclusion, naltrexone and sucrose can reverse increased pain sensitivity and impaired long-term memory induced by acute repetitive neonatal pain probably by normalizing BDNF expression and increasing ß-endorphin levels.

Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension.

Stroke is a leading cause of adult disability worldwide. Improving stroke outcome requires an orchestrated interplay that involves up regulation of pro-survival pathways and a concomitant suppression of pro-apoptotic mediators. In this investigation, we assessed the involvement of eNOS in the AT1 blocker-mediated protective and pro-recovery effects in animals with hypertension. We also evaluated the effect of acute eNOS inhibition in hypertensive animals. To achieve these goals, spontaneously hypertensive rats (SHR) were implanted with blood pressure transmitters, and randomized to receive either an eNOS inhibitor (L-NIO) or saline one hour before cerebral ischemia induction. After 3 hours of ischemia, animals were further randomized to receive either candesartan or saline at the time of reperfusion and sacrificed either 24 hours or 7 days later. Candesartan induced an early protective effect that was independent of eNOS inhibition (50% improvement in motor function). However, the protective effect of candesartan was associated with about five fold up regulation of BDNF expression and about three fold reduction in ER stress markers, in an eNOS dependent manner. The early benefit of a single dose of candesartan, present at 24 hours after stroke, was diminished at 7 days, perhaps due to a failure to induce an angiogenic response in these hypertensive animals. In conclusion, our findings demonstrate an early prorecovery effect of candesartan at both functional and molecular levels. Candesartan induced prorecovery signaling was mediated through eNOS. This effect was not maintained at 7 days after experimental ischemia.

Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke.

Angiotensin type 1 receptor blockers (ARBs) have been shown to be neuroprotective and neurorestorative in experimental stroke. The mechanisms proposed include anti-inflammatory, antiapoptotic effects, as well as stimulation of endogenous trophic factors leading to angiogenesis and neuroplasticity. We aimed to investigate the involvement of the neurotrophin, brain-derived neurotrophic factor (BDNF), in ARB-mediated functional recovery after stroke. To achieve this aim, Wistar rats received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles or nontargeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-min middle cerebral artery occlusion (MCAO) and received the ARB, candesartan, 1 mg/kg, or saline IV at reperfusion (one dose), then followed for another 14 days using a battery of behavioral tests. BDNF protein expression was successfully reduced by about 70 % in both hemispheres at 14 days after bilateral shRNA lentiviral particle injection. The NTC group that received candesartan showed better functional outcome as well as increased vascular density and synaptogenesis as compared to saline treatment. BDNF knockdown abrogated the beneficial effects of candesartan on neurobehavioral outcome, vascular density, and synaptogenesis. In conclusion, BDNF is directly involved in candesartan-mediated functional recovery, angiogenesis, and synaptogenesis.

Erratum to: Artery reopening is required for the neurorestorative effects of angiotensin modulation after experimental stroke.

[This corrects the article DOI: 10.1186/s13231-016-0018-x.].