Anxiolytic and antidepressant like effects of Zamzam water in STZ-induced diabetic rats, targeting oxidative stress, neuroinflammation, BDNF/ERK/CREP pathway with modulation of hypothalamo-pituitary-adrenal axis.

Introduction: Recent studies have reported a strong relationship between diabetes and anxiety- and depression-like behaviors; however, there is a lack of information on the underlying pathophysiology. Alkaline Zamzam water (ZW), which is rich in several trace elements, has neuroprotective properties. This study aimed to investigate the anxiolytic and antidepressant effects of ZW against diabetes-induced behavioral changes and shed light on the possible underlying mechanisms. Methods: Forty-eight rats were divided into four experimental groups (n = 12): group I (control group), group II (Zamzam water group), group III (diabetic group), and group IV (diabetic + Zamzam water group). Diabetes was induced by an intraperitoneal injection of 60 mg/kg streptozotocin (STZ). At the end of the experiment, the forced swimming test (FST) was used to assess depression-like effects. The elevated plus maze test (EPMT) and open field test (OFT) were performed to evaluate anxiety-like behavior. Blood levels of the hypothalamic-pituitary-adrenal (HPA) axis were measured, and prefrontal cortex and hippocampal tissue samples were removed for histological, immunohistochemical, ELISA, and Q-PCR analyses. Results: ZW significantly decreased the immobility time in the FST, indicating an antidepressant effect (p < 0.001). Additionally, ZW significantly improved the OFT and open field entry (OFE) percentages in the EPMT, increasing center crossing and decreasing grooming and fecal boli in the OFT. This indicated an anxiolytic-like effect in diabetic rats with histological improvement. Interestingly, ZW significantly increased prefrontal cortical and hippocampal levels of antioxidant enzymes and the Nrf2/HO-1 pathway. It also modulated the HPA axis by increasing cortisol and corticotropin-releasing hormone (CRH) levels, with a decrease in ACTH and an increase in monoamine neurotransmitters. Furthermore, diabetic rats that received ZW showed a decrease in the inflammatory markers TNF-α and GFAP by immunohistochemistry and in the mRNA levels of NFκB, IL-1ß, and IL6. In addition, ZW downregulated the expression of the BDNF/ERK2/CREP pathway. Conclusion: Our results suggested a neuroprotective effect of ZW against diabetes-induced anxiety- and depression-like behaviors and explored the underlying mechanisms. These findings suggest a promising therapeutic strategy for patients with diabetes who experience anxiety and depression.

Preparedness of Citizens in Al-Madinah City to Deliver Seizure First Aid Measures.

Introduction Epilepsy is a neurologic disease that causes a predisposition to recurrent seizure attacks. It affects a large number of people around the world and in Saudi Arabia. Seizures can be a source of distress for both the affected person and those witnessing them. Thus, being able to deliver first aid is important, as it improves safety and decreases the burden of visits to the emergency room that are unnecessary, since many attacks of seizure can be managed in the community. Weak knowledge regarding seizure first aid measures is reported many times across Saudi Arabia, with a high prevalence of misconceptions. Methods This study employed a descriptive cross-sectional design, utilizing a questionnaire-based approach. The data was collected from a sample of 1871 individuals residing in Al-Madinah City, Saudi Arabia. The participants completed a self-administered online questionnaire and ensured anonymity. The questionnaire used in this study was previously validated and used in another study. We used descriptive statistics to summarize the data, and Chi-square test was employed to establish the association between sociodemographic data and knowledge of seizure first aid. Results Most of the participants were females (70.0%, N=1310), and the majority (76.1%, N=1423) fell within the 18-30 age group. A high percentage were single (71.6%, N=1339), college graduates (64.3%, N=1201), and unemployed (58.7%, N=1099). The study results revealed that 31.9% (N=597) had a good knowledge level of epilepsy, while 68.1% (N=1274) had poor knowledge. Nearly half (48.4%, N=905) believed that epilepsy was caused by genetic factors, and 61.4% (N=1149) of the respondents reported loss of consciousness as the most common clinical symptom of epilepsy. With regards to correct action during seizures, 48.0% (N=899) knew to place the patient on their side, and 85.0% (N=1591) thought calling 997 ("the ambulance") was necessary if seizures lasted over five minutes. The study showed a statistically significant association between the level of education, employment, and knowledge of epilepsy first aid management (p=0.001 and p=0.003, respectively). However, no significant associations were found between gender, age, marital status, and knowledge of epilepsy first aid management (p>0.005). Conclusion The study unveiled poor overall epilepsy knowledge among Al-Madinah City residents, with only 31.9% (N=597) demonstrating good knowledge. This indicates the community's limited ability to respond to seizures. Most citizens were unfamiliar with seizure first-aid, lacking the capability to provide assistance. A significant association was found between education, employment, and epilepsy first aid knowledge. Respondents with higher education had better epilepsy knowledge. Attending epilepsy education courses is vital for enhancing overall awareness and readiness to provide seizure first aid.

Patterns and Sociodemographic Characteristics of Substance Abuse Among the Adult Population in Makkah City, Saudi Arabia: A Cross-Sectional Study.

BACKGROUND: Substance abuse is a term that refers to the harmful or hazardous use of psychoactive substances, including alcohol and illicit drugs. One of the key impacts of illicit drug use on society is the negative health consequences experienced by its members. OBJECTIVE: This study recorded the pattern of substance abuse and the sociodemographic characteristics of adult substance abusers in Makkah City. METHODS: An online self-administered survey was provided to the general population through social media platforms between March 2023 and August 2023. Males and females living in Makkah over the age of 18 were included in it. The participants who refused to take part or those who were younger than 18 were not included in the study. RESULTS: The number of participants in this study was 720; 73.5% were under the age of 30 and 424 were females (58.9%). The significant variables between substance abuse and sociodemographic data were gender (P=0.001), depression (P≤0.000), anxiety (P≤0.000), stress (P=0.025), and bad/shocking experience during childhood (P=0.004). CONCLUSION: Substance abuse positively correlates with sociodemographic data, with males having a higher risk, and psychiatric neurosis is associated with childhood trauma and anxiety.

Novel Insights about Synergistic Effect of Zamzam Water with SGL2 Inhibitors on Wound Healing in STZ-Induced Diabetic Rats: The Role of anti-Inflammatory and Proangiogenic Effects.

Background: Hyperglycemia usually impairs wound healing by dysregulating the inflammatory response and angiogenesis. This study aimed to examine the synergistic effect of dapagliflozin and Zamzam water (ZW) on the healing of diabetic wounds and to explore their anti-inflammatory and proangiogenic effects.Materials and methods: A full-thickness excisional wound was made on the backs of all groups after two weeks of diabetes induction. Forty rats were divided into five groups, with eight rats per group; Group 1: Control non-diabetic rats; Group II: Untreated diabetic rats; Group III: Diabetic rats drinking ZW; Group IV: Diabetic rats receiving an oral dose of 1 mg/kg dapagliflozin; and Group V: Received both dapagliflozin and ZW. The healing of diabetic wounds was assessed by measuring wound closure, oxidative stress markers, immunohistochemical staining of NF-ßB, VEGF, CD34, CD45, Ki-67, and eNOS, gene expression of MMP-9, TGF-ß1, EGF-b1, FGF, and Col1A1, protein levels of TNFα, IL-1ß, IL6, Ang II, and HIF-1α by ELISA assay, and histological examination with H & E and Masson's trichrome. Combined treatment with dapagliflozin and ZW significantly (p < 0.05) enhanced the wound closure and antioxidant enzyme level, with apparent histological improvement, and shortened the inflammatory stage of the diabetic wound by decreasing the level of inflammatory markers NF-κB, TNF-α, IL-1ß, IL6, and CD45. Therefore, it improved angiogenesis markers VEGF, CD34, eNOS, EGF-ß1, FGF, Ang II, and HIF-1α, increasing Ki-67 cellular proliferation. Moreover, it enhanced the remodeling stage by increasing MMP-2, TGF-ß1, and Col1A1 levels compared to diabetic rats.

Association of Migraine Headache With Depression, Anxiety, and Stress in the Population of Makkah City, Saudi Arabia: A Cross-Sectional Study.

Introduction Migraine is characterized by persistent headaches and a wide range of symptoms, such as nausea, vomiting, and photophobia. The chance of developing a chronic migraine might be increased by lifestyle variables like obesity, stress, and excessive medication use. According to previous studies in Saudi Arabia, migraines are more common there than they are globally. The study aimed to examine the migraine associations with depression, anxiety, and stress in the population of Makkah City, Saudi Arabia. Methods The study employed a descriptive cross-sectional design with a non-probability snowball sampling technique and an online questionnaire that included sociodemographic characteristics, the International Classification of Headache Disorders-3 (ICHD-3) criteria for migraine assessment, and the Depression, Anxiety, and Stress Scale-21 (DASS-21) measure for depression, anxiety, and stress. Results Our study included 418 participants, out of whom 73.7% were female and 26.3% were male. Regarding migraine, only 8.9% of participants met the ICHD-3 criteria for migraine headache screening, with a female predominance (78.4%). The study showed a high prevalence of depression, anxiety, and stress among the population (63.9%, 63.6%, and 55%, respectively), with females having a higher prevalence. Depression, anxiety, and stress had an equal prevalence of 78.4% among migraineurs, which was significantly higher than that of non-migraineurs. Conclusions The study found significant associations between migraine and depression, anxiety, and stress. This study provides insights into the association between these conditions. The study's findings suggest the need for screening and management of mental health conditions in patients with migraine. However, extensive efforts are needed to be applied in different cities and demographics for a more precise understanding of the association.

Medication Adherence Status and Its Association With Quality of Life Among Individuals With Neurological Conditions in Saudi Arabia.

INTRODUCTION: Chronic disorders commonly require long-term therapies. Medication non-adherence can cause major morbidity and mortality in chronic illness individuals, as well as increase the financial burden on the healthcare system. It is considered that patients who adhere to their treatment may improve their quality of life (QoL). There is a scarcity of updated comprehensive data on medication adherence among Saudi patients with neurological disorders. Therefore, this study aimed to assess the medication adherence status among individuals with neurological conditions and its association with QoL. METHOD: A cross-sectional questionnaire-based study was conducted. The study included subjects individuals who have neurological conditions aged at least 18 from different regions of Saudi Arabia. The questionnaire measured medication adherence by using the 10-item version of the Medication Adherence Report Scale (MARS-10, ©Professor Rob Horne). The QoL was measured by employing validated Euro Quality of Life 5-dimension scale (EQ-5D). RESULTS: A total of 370 participants were included. Respondents aged 18 to 35 years represented 62.4% of the sample. More than half of the participants were females (65.7%). The most frequently reported chronic conditions were migraine (29.2%), epilepsy (20.8%), and multiple sclerosis (20.5%). The reliability of the EQ-5D questionnaire was acceptable (Cronbach's alpha = 0.764). In general, more than half of the participants indicated that had problems due to pain/discomfort (60.3%) and anxiety/depression (62.2%). The most common pattern of non-adherence was taking the medication only when a patient needed it followed by avoiding taking the medication as possible. Non-adherence to medications was less prevalent among participants with epilepsy (68.8%) and multiple sclerosis (65.8%). On the other hand, medication adherence was higher among respondents with migraine compared to participants without the condition (86.1% vs 73.7%, p = 0.009). A significantly lower proportion of participants who had some or extreme problems with self-care were non-adherent to medications compared to those who had no problems (68.1% vs 80.3%, respectively, p = 0.016). Results of the regression analysis showed that participants with epilepsy and multiple sclerosis were less likely to be non-adherence to medications. Furthermore, respondents with moderate and severe problems in self-care were less likely to be non-adherent. CONCLUSION: It was found that more than half of the participants had problems regarding their QoL due to pain/discomfort and anxiety/depression. The most prevalent pattern of non-adherence was taking the medication only when needed. Participants with epilepsy and multiple sclerosis were less likely to be non-adherent to medications. Furthermore, respondents with moderate and severe problems in self-care were less likely to be non-adherent. We recommend serial studies on the issue should be conducted to gather more evidence regarding this topic.

Exploring the Therapeutic Potential of Apigenin in Obesity-Associated Fibrinolytic Dysfunction: Insights From an Animal Study.

INTRODUCTION: Obesity (Obe) is a chronic metabolic disorder usually complicated by impaired fibrinolytic activity. Apigenin (Api) is one of the flavonoids that have anti-adiposity effects. This study aimed to explore the therapeutic potential of Api in high-fat diet (HFD)-induced obese rats. METHODS: Twenty-four Wistar adult male rats were randomly allocated into control group, supplemented with a normal pellet diet (NPD); Api group, supplemented with Api (10 mg/kg) for eight weeks; Obe group, obesity was induced by feeding HFD for eight weeks; and Obe/Api group, obese rats supplemented with Api for eight weeks. Body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), total superoxide dismutase (t-SOD) activity, and plasminogen activator inhibitor-1 (PAI-1) were measured. RESULTS: Compared to the control group, Obe group exhibited a significant increase in BMI, HOMA-IR, TNF-α, MDA, and PAI-1. These results were also associated with a significant decrease in serum t-SOD activity. Supplementation of Api alleviated the measured deteriorated parameters and ameliorated visceral adiposity in obese rats. CONCLUSION: This study provides compelling evidence regarding a promising role for Api in ameliorating the impairment of fibrinolytic activity in an Obe animal model. The observed effects are likely mediated through Api's anti-obesity properties, as well as its indirect modulation of PAI-1, oxidative stress, and inflammation. Future clinical studies are recommended that may make benefit of the preclinical therapeutic use of apigenin in obesity-associated fibrinolytic dysfunctions.

Assessment of Barriers and Challenges in Headache Education Among Neurology Residents in Saudi Arabia.

Background  Headache problems are among the most common medical conditions. There are major gaps in understanding headaches among healthcare practitioners. This study aimed to determine challenges and barriers to headache training among neurology residents in Saudi Arabia. Methods  A cross-sectional questionnaire-based study was conducted in Saudi Arabia. The target population was all Saudi neurology residents who were currently registered with the Saudi Commission for Health Specialties (SCHS). Statistical analysis was conducted using RStudio (R version 4.1.1). A chi-squared test is used for categorical variables whenever applicable. The statistical differences for continuous variables were assessed using a Wilcoxon rank sum test. Results A total of 227 respondents were included. More than half of the residents were male (56.8%). Large proportions of residents self-rated their knowledge as good for migraines (62.6%) and tension-type headaches (60.4%). The most experienced challenges included difficult diagnosis (30.4%) and treatment difficulties due to comorbidities (19.8%). The most stated barriers to optimal treatment of headache patients were the existence of challenges in collaboration between patient and therapist (24.7%). Most residents rely on the use of the International Classification of Headache Disorders (ICHD) in diagnosing and managing headache patients instead of the Saudi guidelines. The most reported reason for headache referral was suspicion of an underlying serious disease (31.7%). The most recommended non-pharmacological interventions were exercise (15.9%). Conclusion  We found that residents reported the diagnosis of headache as the most challenging barrier. The overuse of analgesics played a role in causing the headache. The most often cited barrier to providing headache patients with the best possible care was difficulties in patient-therapist collaboration. Ongoing headache education and comprehensive academic training are recommended to enhance knowledge during neurology residency training and offer competent care for their patients.

Phytochemical analysis of Origanum majorana L. extract and investigation of its antioxidant, anti-inflammatory and immunomodulatory effects against experimentally induced colitis downregulating Th17 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Origanum majorana L. is a member of the Lamiaceae family and is commonly used in Egyptian cuisine as a seasoning and flavor enhancer. It is also recognized as a well-known traditional medicine in Egypt and is widely used for treating abdominal colic due to its antispasmodic properties. However, the protective effects of Origanum majorana L. against ulcerative colitis and its underlying mechanisms remain unclear. AIM OF THE STUDY: This study aimed to identify the biologically active components present in methanol extracts of Origanum majorana L. using gas chromatography/mass spectrometry (GC/MS). Additionally, it aimed to investigate the therapeutic effects of these extracts on acetic acid-induced ulcerative colitis and elucidate the potential mechanisms involved. MATERIALS AND METHODS: We conducted a GC-MS analysis of the methanolic extract obtained from Origanum majorana L. Thirty-two male rats were included in the study and divided into four experimental groups, with eight rats in each group: sham, UC, UC + O. majorana, and UC sulfasalazine. After euthanizing the rats, colon tissue samples were collected for gross and microscopic examinations, assessment of oxidative stress, and molecular evaluation. GC-MS analysis identified 15 components in the extracts. Pretreatment with O. majorana L. extract and sulfasalazine significantly improved the disease activity index (DAI) and resulted in notable improvements in macroscopic and microscopic colon findings. Additionally, both treatments demonstrated preventive effects against colonic oxidative damage by reducing the levels of malondialdehyde (MDA) and increasing the levels of the antioxidant systems superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), which operate through the Nrf2/HO-1 signaling pathway. Moreover, these treatments downregulated the colonic inflammatory cascade by inhibiting NFκB, TNFα, IL-1ß, IL6, IL23, IL17, COX-2, and iNOS, subsequently leading to downregulation of the JAK2/STAT3 signaling pathway and a decrease in the Th17 cell response. Furthermore, a reduction in the number of apoptotic epithelial cells that expressed caspase-3 was observed. CONCLUSION: pretreatment with O. majorana L. extract significantly ameliorated acetic acid-induced ulcerative colitis. This effect could be attributed to the protective, antioxidant, anti-inflammatory, and anti-apoptotic properties of the extract.

Knowledge and Awareness of Parents About the Difference Between Attention Deficit Hyperactivity Disorder and Childhood Absence Epilepsy in the Paediatric Population Makkah, Saudi Arabia: A Cross-Sectional Study.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder, mainly in children. The signs and symptoms of ADHD include inattention, impulsivity, and hyperactivity. Consequently, Childhood Absence Epilepsy (CAE) tends to present in children with sudden and recurrent episodes of loss of awareness alongside symptoms that occasionally include clonic, atonic, and simple automatisms. The present study evaluates parents' knowledge in Makkah regarding the difference between ADHD and CAE. METHODOLOGY: The study was conducted among Saudi Arabian parents living in Makkah. Data were collected in April 2022 through the use of an online survey that was distributed electronically via social media platforms. The inclusion criteria entailed parents from different socio-economic backgrounds. In contrast, the exclusion criteria entailed parents who had not been involved in raising their children and those with children with intellectual disabilities. A group of consultants was tasked with validating all data collected through an original questionnaire. To effectively calculate the study sample size, OpenEpi Version 3.01 was used. Lastly, all statistical analyses were conducted with Stata Social Sciences (SPSS®) software for Mac, version 26 (IBM Corp., Armonk, NY, USA). RESULTS: A total of 633 participants completed the survey. Of the total respondents, approximately 1% indicated having a good knowledge level, 15.17% indicated having moderate knowledge, and the remaining 84% indicated poor knowledge of the subject under study. Approximately 46% of the participants reported that social media was the primary source of information. One significant issue regards the observation that the parent's level of education was statistically associated with the level of knowledge. CONCLUSION: There is limited awareness of the difference between (ADHD) and (CAE) among parents in the pediatric population. These findings highlight an opportunity to raise awareness using well-organized education programs in Makkah City.

Assessment of the Prevalence and Level of Awareness of Medication Overuse Headache Among the General Population in Makkah City, Saudi Arabia.

BACKGROUND: Medication overuse headache (MOH) is a secondary headache condition caused by consistently using more medication than necessary to treat headache symptoms. MOH is defined as a headache that occurs for 15 or more days per month in a patient with a pre-existing primary headache, and it develops as a result of regular overuse of symptomatic headache medication for more than three months. Patients with headaches often use simple pain medication for 15 or more days per month (e.g., non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol) and 10 or more days per month of opioids, triptans, and combination analgesics, but when there is no relief from these medications, the headache progression can lead to a cycle of consuming more medication with increased pain, which can lead to MOH. OBJECTIVE: This study aimed to assess the prevalence and awareness of MOH among the general population of Makkah, Saudi Arabia. METHODS: A cross-sectional study was conducted between December 2022 and March 2023 using a self-administered online questionnaire disseminated through social media. Data were collected from females and males 18 years of age and older living in Makkah, Saudi Arabia. RESULTS: Overall, 715 individuals completed the questionnaire, 497 of whom were female (69.5%). The average age of the participants was 32.9 years (±13.3 years). The prevalence of MOH among those who reported having experienced headaches throughout their lifetimes was estimated to be 4.5%. Only 134 people (18.7%) were determined to be aware of MOH. CONCLUSION: This study demonstrated that the general population of Makkah has a high prevalence of MOH and low levels of MOH awareness.

Palliative Role of Zamzam Water against Cyclosporine-Induced Nephrotoxicity through Modulating Autophagy and Apoptosis Crosstalk.

Cyclosporine (CsA) is considered one of the main components of treatment protocols for organ transplantation owing to its immunosuppressive effect. However, its use is very restricted due to its nephrotoxic effect. ZW is an alkaline fluid rich in various trace elements and has a great ability to stimulate antioxidant processes. This study aimed to investigate the possible mitigating effect of ZW on CsA-induced nephrotoxicity and its underlying mechanisms. Forty rats were allocated into four groups (n = 10): a control group, ZW group, cyclosporine A group (injected subcutaneously (SC) with CsA (20 mg/kg/day)), and cyclosporine A+ Zamzam water group (administered CsA (SC) and ZW as their only drinking water (100 mL/cage/day) for 21 days). Exposure to CsA significantly (p < 0.001) increased the serum creatinine level, lipid peroxidation marker level (malondialdehyde; MDA), and the expression of apoptotic markers procaspase-8, caspase-8, caspase- 9, calpain, cytochrome c, caspas-3, P62, and mTOR in renal tissues. Meanwhile, it markedly decreased (p< 0.001) the autophagic markers (AMPK, ULK-I, ATag5, LC3, and Beclin-1), antiapoptotic Bcl-2, and antioxidant enzymes. Moreover, the administration of CsA caused histological alterations in renal tissues. ZW significantly (p < 0.001) reversed all the changes caused by CsA and conclusively achieved a positive outcome in restraining CsA-induced nephrotoxicity, as indicated by the restoration of the histological architecture, improvement of renal function, inhibition of apoptosis, and enhancement of autophagy via the AMPK/mTOR pathway.

Diacerein mitigates renal ischemia/reperfusion injury via inhibition of renal inflammation, dendritic cells maturation and apoptosis: the role of TLR4/NF-kB/NLRP3/IL-1beta signaling pathway / La diacereína mitiga la lesión por isquemia/reperfusión renal a través de la inhibición de la inflamación renal, la maduración de las células dendríticas y la apoptosis: el papel de la vía de señalización TLR4/NF-kB/NLRP3/IL-1beta

SUMMARY: One of the reasons for acute kidney damage is renal ischemia. Nevertheless, there are limited protective and therapeutic approaches for this problem. Diacerein is an anti-inflammatory drug characterized by numerous biological activities. We aimed to determine the ameliorative impact of diacerein on renal ischemia/reperfusion injury (I/R) condition, exploring the underlying mechanisms. Twenty-four male rats were allotted into four groups (n= 6): sham group; Diacerein (DIA) group; I/R group, in which a non-crushing clamp occluded the left renal pedicle for 45 min, and the right kidney was nephrectomized for 5 min before the reperfusion process; I/R + diacerein group, injected intraperitoneally with 50 mg diacerein/kg i.m 30 minutes prior to I/R operation. Ischemia/ reperfusion was found to affect renal function and induce histopathological alterations. The flow cytometry analysis demonstrated an elevated expression of innate and mature dendritic cells in I/R renal tissues. Moreover, upregulation in the expression of the inflammatory genes (TLR4, Myd88, and NLRP3), and overexpression of the pro-inflammatory cytokines (IL-1β), apoptotic (caspase-3) and pyroptotic (caspase-1) markers were observed in I/R-experienced animals. The aforementioned deteriorations were mitigated by pre-I/R diacerein treatment. Diacerein alleviated I/R-induced inflammation and apoptosis. Thus, it could be a promising protective agent against I/R.

La isquemia renal es una de los motivos del daño renal agudo. Sin embargo, los enfoques protectores y terapéuticos para este problema son limitados. La diacereína es un fármaco antiinflamatorio caracterizado por numerosas actividades biológicas. Nuestro objetivo fue determinar el impacto de mejora de la diacereína en la condición de lesión por isquemia/ reperfusión renal (I/R), explorando los mecanismos subyacentes. Veinticuatro ratas macho se distribuyeron en cuatro grupos (n= 6): grupo simulado; grupo de diacereína (DIA); grupo I/R, en el que una pinza no aplastante ocluyó el pedículo renal izquierdo durante 45 min, y el riñón derecho fue nefrectomizado durante 5 min antes del proceso de reperfusión; Grupo I/R + diacereína, inyectado por vía intraperitoneal con 50 mg de diacereína/kg i.m. 30 min antes de la operación I/R. Se encontró que la isquemia/ reperfusión afecta la función renal e induce alteraciones histopatológicas. El análisis de citometría de flujo demostró una expresión elevada de células dendríticas innatas y maduras en tejidos renales I/R. Además, se observó una regulación positiva en la expresión de los genes inflamatorios (TLR4, Myd88 y NLRP3) y una sobreexpresión de las citoquinas proinflamatorias (IL-1β), marcadores apoptóticos (caspasa-3) y piroptóticos (caspasa-1) en animales con experiencia en I/R. Los deterioros antes mencionados fueron mitigados por el tratamiento previo a la diacereína I/R. La diacereína alivió la inflamación y la apoptosis inducidas por I/R. Por lo tanto, podría ser un agente protector prometedor contra I/R.

Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism.

BACKGROUND: γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain where it regulates activity of neuronal networks. The receptor for glucagon-like peptide-1 (GLP-1) is expressed in the hippocampus, which is the center for memory and learning. In this study we examined effects of liraglutide, a GLP-1 analog, on GABA signaling in CA3 hippocampal pyramidal neurons. METHODS: We used patch-clamp electrophysiology to record synaptic and tonic GABA-activated currents in CA3 pyramidal neurons in rat hippocampal brain slices. RESULTS: We examined the effects of liraglutide on the neurons at concentrations ranging from one nM to one µM. Significant changes of the spontaneous inhibitory postsynaptic currents (sIPSCs) were only recorded with 100 nM liraglutide and then in just ≈50% of the neurons tested at this concentration. In neurons affected by liraglutide both the sIPSC frequency and the most probable amplitudes increased. When the action potential firing was inhibited by tetrodotoxin (TTX) the frequency and amplitude of IPSCs in TTX and in TTX plus 100 nM liraglutide were similar. CONCLUSIONS: The results demonstrate that liraglutide regulation of GABA signaling of CA3 pyramidal neurons is predominantly presynaptic and more limited than has been observed for GLP-1 and exendin-4 in hippocampal neurons.

GLP-1 and exendin-4 transiently enhance GABAA receptor-mediated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons.

Glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippocampus, the center for memory and learning. Diabetes is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on γ-aminobutyric acid (GABA) signaling in hippocampal CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01-1 nmol/L) transiently enhanced synaptic and tonic currents, and the effects were blocked by exendin (9-39). Ten pmol/L GLP-1 increased both the spontaneous inhibitory postsynaptic current (sIPSC) amplitudes and frequency by a factor of 1.8. In 0.1, 1 nmol/L GLP-1 or 10, 50, or 100 nmol/L exendin-4, only the sIPSC frequency increased. The tonic current was enhanced by 0.01-1 nmol/L GLP-1 and by 0.5-100 nmol/L exendin-4. When action potentials were inhibited by tetrodotoxin (TTX), inhibitory postsynaptic currents decreased and currents were no longer potentiated by GLP-1 or exendin-4. In contrast, although the tonic current decreased in TTX, it was still enhanced by GLP-1 or exendin-4. The results demonstrate GLP-1 receptor regulation of hippocampal function and are consistent with GLP-1 receptor agonists enhancing GABAA signaling by pre- and postsynaptic mechanisms.

Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from human glioblastoma.

GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, ß1, ß2, ß3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36 µM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1 µM) and the general anesthetics etomidate and propofol (50 µM). In line with the expressed GABAA receptors containing at least the α3ß3θ subunits, the receptors were highly sensitive to etomidate (EC50=55 nM). Immunocytochemistry identified expression of the α3 and ß3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.