Involvement of Autophagic Machinery in Neuropathogenesis: Targeting and Relevant Methods of Detection.

The exquisite balance between cellular prosurvival and death pathways is extremely necessary for homeostasis. Different forms of programmed cell death have been widely studied and reported such as apoptosis, necroptosis, pyroptosis, and autophagy. Autophagy is a catabolic process important for normal cellular functioning. The main aim of this machinery is to degrade the misfolded or damaged proteins, unuseful organelles, and pathogens, which invade the cells, thereby maintaining cellular homeostasis and assuring the regular renewal of cell components. This prosurvival function of autophagy highlights its importance in many human diseases, as the disturbance of this tightly organized process ultimately causes detrimental effects. Interestingly, neurons are particularly susceptible to damage upon the presence of any alteration in the basal level of the autophagic activity; this could be due to their high metabolic demand, post-mitotic nature, and the contribution of autophagy in the different fundamental functions of neurons. Herein, we have reported the role of autophagy in different CNS disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and epilepsy, besides the pharmacological agents targeting autophagy. Due to the significant contribution of autophagy in the pathogenesis of many diseases, it is crucial to develop effective methods to detect this dynamic process. In this chapter, we have summarized the most frequently employed techniques in studying and detecting autophagy including electron microscopy, fluorescence microscopy, Western blotting, intracellular protein degradation, and sequestration assay.

Metabolomics-directed nanotechnology in viral diseases management: COVID-19 a case study.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently regarded as the twenty-first century's plague accounting for coronavirus disease 2019 (COVID-19). Besides its reported symptoms affecting the respiratory tract, it was found to alter several metabolic pathways inside the body. Nanoparticles proved to combat viral infections including COVID-19 to demonstrate great success in developing vaccines based on mRNA technology. However, various types of nanoparticles can affect the host metabolome. Considering the increasing proportion of nano-based vaccines, this review compiles and analyses how COVID-19 and nanoparticles affect lipids, amino acids, and carbohydrates metabolism. A search was conducted on PubMed, ScienceDirect, Web of Science for available information on the interrelationship between metabolomics and immunity in the context of SARS-CoV-2 infection and the effect of nanoparticles on metabolite levels. It was clear that SARS-CoV-2 disrupted several pathways to ensure a sufficient supply of its building blocks to facilitate its replication. Such information can help in developing treatment strategies against viral infections and COVID-19 based on interventions that overcome these metabolic changes. Furthermore, it showed that even drug-free nanoparticles can exert an influence on biological systems as evidenced by metabolomics.

Modulatory effect of liraglutide on doxorubicin-induced testicular toxicity and behavioral abnormalities in rats: role of testicular-brain axis.

Doxorubicin (DOX) is a powerful chemotherapeutic agent used in many types of malignancies. However, its use results in testicular damage. DOX-induced testicular damage results in low level of serum testosterone which may affect cognitive function. The current study investigated the protective effect of liraglutide (50, 100 µg/kg/day) in testicular toxicity and the consequent cognitive impairment induced by DOX. DOX treatment reduced sperm count (62%) and sperm motility (53%) and increased sperm abnormalities (786%), as compared to control group. DOX also reduced serum testosterone level (85%) and the gene expression of testicular 3ß-HSD (68%) and 17ß-HSD (82%). Moreover, it increased testicular oxidative stress (MDA and GSH) by 103% and 59%, respectively, apoptotic (caspase-3 and P53) by 996% and 480%, respectively. In addition, DOX resulted in increasing autophagic markers including PAKT, mTOR, and LC3 by 48%, 56%, and 640%, respectively. Additionally, rats' behavior in Y-maze (60%) and passive avoidance task (85%) was disrupted. The histopathological results of testis and brain supported the biochemical findings. Treatment with liraglutide (100 µg/kg/day) significantly abrogated DOX-induced testicular damage by restoring testicular architecture, increasing sperm count (136%) and sperm motility (106%), and decreasing sperm abnormalities (84%) as compared to DOX group. Furthermore, liraglutide increased serum testosterone (500%) and steroidogenesis enzymes 3ß-HSD (105%) and 17ß-HSD (181%) along with suppressing oxidative stress (MDA and GSH) by 23% and 85%, respectively; apoptotic (caspase-3 and P53) by 59% and55%, respectively; and autophagic markers including PAKT, mTOR, and LC3 by 48%, 97%, and 60%, respectively. Moreover, it enhanced the memory functions in passive avoidance and Y-maze tests (132%). In conclusion, liraglutide is a putative agent for protection against DOX-induced testicular toxicity and cognitive impairment through its antioxidant, antiapoptotic, and antiautophagic effects.

Neuroprotective repositioning and anti-tau effect of carvedilol on rotenone induced neurotoxicity in rats: Insights from an insilico& in vivo anti-Parkinson's disease study.

Current treatments for Parkinson's Disease (PD) only provide symptomatic relief; however, they don't delay the disease progression, hence new treatment options should be considered. Carvedilol is a nonselective ß & α1 blocker with additional effects as an antioxidant, anti-inflammatory and neuro protective properties. In this research, an insilico study was conducted to primarily evaluate carvedilol as an anti-parkinsonian and anti-tau protein target. PASS prediction was performed followed by a docking study of carvedilol. Carvedilol yielded promising results and forward guided this study onto its in vivo evaluation. The in vivo study aimed to assess the neuro-protective effects of carvedilol in rotenone-induced rat model of PD and investigate the potential underlying mechanisms. The effects of carvedilol (2.5, 5, and 10 mg/kg) on the measured parameters of open field, catalepsy, Y-maze tests as well as brain histology, and tyrosine hydroxylase (TH) were evaluated. The effective doses (5 and 10 mg/kg) were further tested for their potential anti-tau protein effects. Carvedilol (5 and 10 mg/kg) prevented rotenone-induced motor deficits, spatial memory dysfunction, and histological damage. Additionally, carvedilol significantly inhibited rotenone-induced decrease in TH expression in the striata of the rats. These effects were associated with reduction of rotenone-induced neuro-inflammation, microglial activation and release of glial fibrillary acidic protein (GFAP), along with reduction in N-methyl-D-aspartate receptors activation, alpha-synculein and phospho-Tau (P-Tau) protein expression. Carvedilol also reduced tau protein hyper-phosphosrylation by Glycogen synthase 3ß (GSK 3ß) inhibition and Phosphoinositide 3-kinase (PI3K) stimulation. Collectively, these results suggest that carvedilol might be a possible candidate for management of PD.

Glimepiride mitigates tauopathy and neuroinflammation in P301S transgenic mice: role of AKT/GSK3ß signaling.

BACKGROUND AND OBJECTIVE: Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study. METHODS: P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests. RESULTS: GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3ß, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels. CONCLUSION: The current data suggests that GPD exerts a protective effect against tauopathy, behavioural consequences, neurodegeneration, neuroinflammation and apoptosis. GPD is therefore a promising agent for the treatment of neurodegenerative diseases associated with tauopathy.

Potential role of Drug Repositioning Strategy (DRS) for management of tauopathy.

Tauopathy is a term that has been used to represent a pathological condition in which hyperphosphorylated tau protein aggregates in neurons and glia which results in neurodegeneration, synapse loss and dysfunction and cognitive impairments. Recently, drug repositioning strategy (DRS) becomes a promising field and an alternative approach to advancing new treatments from actually developed and FDA approved drugs for an indication other than the indication it was originally intended for. This paradigm provides an advantage because the safety of the candidate compound has already been established, which abolishes the need for further preclinical safety testing and thus substantially reduces the time and cost involved in progressing of clinical trials. In the present review, we focused on correlation between tauopathy and common diseases as type 2 diabetes mellitus and the global virus COVID-19 and how tau pathology can aggravate development of these diseases in addition to how these diseases can be a risk factor for development of tauopathy. Moreover, correlation between COVID-19 and type 2 diabetes mellitus was also discussed. Therefore, repositioning of a drug in the daily clinical practice of patients to manage or prevent two or more diseases at the same time with lower side effects and drug-drug interactions is a promising idea. This review concluded the results of pre-clinical and clinical studies applied on antidiabetics, COVID-19 medications, antihypertensives, antidepressants and cholesterol lowering drugs for possible drug repositioning for management of tauopathy.

The diuretic amiloride attenuates doxorubicin-induced chemobrain in rats: Behavioral and mechanistic study.

Cognitive impairment or "chemobrain" is a troublesome adverse effect which had been increasingly reported by cancer patients after doxorubicin (DOX) chemotherapy. Notably, Hypertension, a very common comorbidity in cancer patients, could pose a greater risk for negative cognitive outcomes. Amiloride (AML) is an antihypertensive, potassium-sparing diuretic that has been proven to be neuroprotective in different experimental models; this can be attributed to its ability to inhibit different ion transporters such as Na+/H+ exchanger (NHE), which upon excessive activation can result in intracellular cationic overload, followed by oxidative damage and cellular death. Accordingly, this study was designed to investigate the potential neuroprotective effect of AML against DOX-induced chemobrain and to elucidate possible underlying mechanisms. Briefly, Histopathological examination and neurobehavioral testing (Morris water maze, Y maze and passive avoidance test) showed that AML co-treatment (10 mg/kg/day) markedly attenuated DOX (2 mg/kg/week)-induced neurodegeneration and memory impairment after 4 weeks of treatments. We found that DOX administration up-regulated NHE expression and increased lactic acid content in the hippocampus which were markedly opposed by AML. Moreover, AML mitigated DOX-induced neuroinflammation and decreased hippocampal tumor necrosis factor-α level, nuclear factor kappa-B, and cyclooxygenase-2 expression. Additionally, AML counteracted DOX-induced hippocampal oxidative stress as indicated by normalized malondialdehyde and glutathione levels. Furthermore, AML halted DOX-induced hippocampal apoptosis as evidenced by decreased caspase-3 activity and lower cytochrome c immunoexpression. Our results in addition to the previously reported antitumor effects of AML and its ability to mitigate cancer resistance to DOX therapy could point toward possible new repositioning scenarios of the diuretic AML especially regarding hypertensive cancer patients.

Over a century since ephedrine discovery: an updated revisit to its pharmacological aspects, functionality and toxicity in comparison to its herbal extracts.

Ephedrine, a sympathomimetic amine that exhibits several adrenaline actions, is a plant alkaloid that is a common ingredient in several cold, asthma and narcolepsy treatment preparations, and in obesity management and sport medicine. Its principal action mechanism relies on its direct adrenergic actions as well as indirect role that involves the release of epinephrine and norepinephrine, thus increasing the activity of epinephrine and norepinephrine at the postsynaptic α and ß receptors. Nevertheless, its serious side effects, including stroke, heart attack, drug abuse and interactions, have never been comprehensively reviewed. We conducted a systematic review of data on ephedrine, including its occurrence in functional foods, pharmacological aspects, metabolism, pharmaco/toxicokinetics and clinical features. Furthermore, a review of ephedrine natural structural analogues with regards to their differential adrenergic receptor binding affinities, food interaction, and their impact on the pharmacokinetics and effects relative to ephedrine are presented for the first time, and in comparison to its action when present in herbs.

Piceatannol ameliorates behavioural, biochemical and histological aspects in cisplatin-induced peripheral neuropathy in rats.

Peripheral neurotoxicity is a dose-limiting and a potentially lifelong persistent toxicity of cisplatin. This study investigated the possible protective effect of piceatannol (PIC) in a model of cisplatin-induced peripheral neuropathy in rats. PIC (10 mg/kg, i.p.) was given for 7 days, starting 2 days before cisplatin single injection (7 mg/kg, i.p.). Behavioural, biochemical and histological examinations were conducted. Cisplatin administration resulted in thermal hypoalgesia evidenced by increased paw and tail withdrawal latency times in the hotplate and tail flick tests, respectively, and reduced the abdominal constrictions in response to the acetic acid injection. Moreover, cisplatin treatment decreased rat locomotor activity and grip strength. These behavioural alterations were reversed by PIC coadministration. In addition, PIC decreased cisplatin-induced elevation in serum neurotensin and platinum accumulation in sciatic nerve. Also, PIC reversed, to a large extent, cisplatin-induced microscopical alterations in nerve axons and restored normal myelin thickness. Therefore, PIC may protect against cisplatin-induced peripheral neuropathy.

Role of inflammatory, oxidative, and ER stress signaling in the neuroprotective effect of atorvastatin against doxorubicin-induced cognitive impairment in rats.

Doxorubicin (DOX) is a potent chemotherapeutic agent widely used for the treatment of several malignancies. Despite its effectiveness, DOX has been implicated in induced neurotoxicity manifested as cognitive dysfunction with varying degrees, commonly referred to as chemobrain. DOX-induced chemobrain is presumed to be due to cytokine-induced inflammatory, oxidative, and apoptotic responses damaging the brain. Atorvastatin (ATV), 3-hydroxy 3-methylglutaryl co-enzyme A (HMG Co-A) reductase inhibitor, is a cholesterol-lowering statin possessing beneficial pleiotropic effects, including anti-inflammatory, antioxidant, and anti-apoptotic properties. Therefore, this study aims to investigate the potential neuroprotective effects of ATV against DOX-induced cognitive impairment studying the possible involvement of heme oxygenase-1 (HO-1) and endoplasmic reticulum (ER) stress biomarkers. Rats were treated with DOX (2 mg/kg/week), i.p. for 4 weeks. Oral treatment with ATV (10 mg/kg) ameliorated DOX-induced behavioral alterations, protected brain histological features, and attenuated DOX-induced inflammatory, oxidative, and apoptotic biomarkers. In addition, ATV upregulated the protective HO-1 expression levels and downregulated the DOX-induced apoptotic ER stress biomarkers. In conclusion, ATV (10 mg/kg) exhibited neuroprotective properties against DOX-induced cognitive impairment which could possibly be attributed to their anti-inflammatory, antioxidant, and anti-apoptotic effects in the brain.

'Methyl palmitate attenuates adjuvant induced arthritis in rats by decrease of CD68 synovial macrophages.

The study was designed to investigate the potential anti-arthritic effects of methyl palmitate in an adjuvant arthritis model in rats that shares many histopathological similarities with human RA. The underlying mechanism and its effect on CD68 macrophages were investigated, as a further argument to its possible efficacy in RA treatment. A normal control group was injected only with saline, arthritic group, and three treatment groups with CFA induced arthritis received methyl palmitate (MP) at three different doses (75, 150, 300 mg/kg/week for 3 weeks, intraperitoneal). The degree of ipsilateral paw swelling, ankle diameter, spleen index, thymus index and the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß were measured. In addition, the underlying molecular mechanism was investigated using CD68 expression. Methyl palpitate significantly and dose dependently decreased the arthritic symptoms as measured by ipsilateral paw volume and ankle diameter. It showed no effect on body weight but significantly decreased splenic, thymus index, serum TNF-α and IL-1ß. CD68 macrophages expression and the overall synovial inflammatory cellularity were halted. Methyl palmitate exhibits significant anti-inflammatory and exerts a potential anti-arthritic effect in a rat model of adjuvant induced arthritis. Furthermore, it inhibits expression of synovial CD68 macrophage that validate its therapeutic potential adjuvant arthritis.

Chemotherapy-induced cognitive impairment (CICI): An overview of etiology and pathogenesis.

Many cancer patients treated with chemotherapy develop chemotherapy-induced cognitive impairment (CICI), often referred to as chemo-brain, which manifest during or post-treatment with variable degrees, onset and duration thereby affecting the patients' quality of life. Several chemotherapeutic agents have been studied to determine its possible association with cognitive impairment and to fully comprehend their contribution to CICI. A vast number of studies have emerged proposing several candidate underlying mechanisms and etiologies contributing to CICI such as direct neurotoxicity, BBB disruption, decreased hippocampal neurogenesis, white matter abnormalities, secondary neuro-inflammatory response and increased oxidative stress; however, the exact underlying mechanisms are still not well defined. This review summarizes CICI associated with most commonly used chemotherapeutic agents with emphasizes the possible underlying pathogenesis in both animal and clinical studies.

Repurposing of Secukinumab as Neuroprotective in Cuprizone-Induced Multiple Sclerosis Experimental Model via Inhibition of Oxidative, Inflammatory, and Neurodegenerative Signaling.

Multiple sclerosis (MS) is a chronic, inflammatory, and neurodegenerative autoimmune disease. MS is a devastating disorder that is characterized by cognitive and motor deficits. Cuprizone-induced demyelination is the most widely experimental model used for MS. Cuprizone is a copper chelator that is well characterized by microgliosis and astrogliosis and is reproducible for demyelination and remyelination. Secukinumab (SEC) is a fully human monoclonal anti-human antibody of the IgG1/kappa isotype that selectively targets IL-17A. Expression of IL-17 is associated with MS. Also, IL-17 stimulates microglia and astrocytes resulting in progression of MS through chemokine production and neutrophil recruitment. This study aimed to investigate the neuroprotective effects of SEC on cuprizone-induced demyelination with examining the underlying mechanisms. Locomotor activity, short-term spatial memory function, staining by Luxol Fast Blue, myelin basic protein, gliasosis, inflammatory, and oxidative-stress markers were assessed to evaluate neuroprotective, anti-inflammatory and antioxidant effects. Moreover, the safety profile of SEC was evaluated. The present study concludes the efficacy of SEC in Cup-induced demyelination experimental model. Interestingly, SEC had neuroprotective and antioxidant effects besides its anti-inflammatory effect in the studied experimental model of MS. Graphical abstract.

Abrogating doxorubicin-induced chemobrain by immunomodulators IFN-beta 1a or infliximab: Insights to neuroimmune mechanistic hallmarks.

Chemobrain is a well-established clinical syndrome that impairs patient's daily function, in particular attentiveness, coordination and multi-tasking. Thus, it interferes with patient's quality of life. The putative pharmacological intervention against chemobrain relies on understanding the molecular mechanisms underlying it. This study aimed to examine the potential neuroprotective effects of two immunomodulators: Interferon-ß-1a (IFN-ß-1a), as well as Tumor necrosis function-alpha (TNF-α) inhibitor; Infliximab in doxorubicin (DOX)-induced chemobrain in rats. Besides, the current study targets investigating the possible molecular mechanisms in terms of neuromodulation and interference with different death routes controlling neural homeostasis. Herein, the two immunomodulators IFN-ß-1a at a dose of 300,000 units; s.c.three times per week, or Infliximab at a dose of 5 mg/kg/week; i.p. once per week were examined against DOX (2 mg/kg/w, i.p.) once per week for 4 consecutive weeks in rats.The consequent behavioral tests and markers for cognitive impairment, oxidative stress, neuroinflammation, apoptosis and neurobiological abnormalities were further evaluated. Briefly, IFN-ß-1a or Infliximab significantly protected against DOX-induced chemobrain. IFN-ß-1a or Infliximab ameliorated DOX-induced hippocampal histopathological neurodegenerative changes, halted DOX-induced cognitive impairment, abrogated DOX-induced mitochondrial oxidative, inflammatory and apoptotic stress, mitigated DOX-induced autophagic dysfunction and finally upregulated the mitophagic machineries. In conclusion, these findings suggest that either IFN-ß-1a or Infliximab offers neuroprotection against DOX-induced chemobrain which could be explained by their antioxidant, anti-inflammatory, pro-autophagic, pro-mitophagic and antiapoptotic effects. Future clinical studies are recommended to personalize either use of IFN-ß-1a or infliximab to ameliorate DOX-induced chemobrain.

Role of linagliptin in preventing the pathological progression of hepatic fibrosis in high fat diet and streptozotocin-induced diabetic obese rats.

Liver fibrosis is a common complication of diabetes mellitus, with a major global public health concern. Linagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4), is classically used to treat type 2 diabetes mellitus and improves insulin resistance. Additional potential influences of linagliptin on liver fibrosis are still unclear. The present study was undertaken to investigate the therapeutic credit of linagliptin in hepatic fibrosis induced by a high-fat diet (HFD) and streptozotocin (STZ) in rats. Moreover, the mechanisms underline its anti-fibrotic effect were explored. To induce liver fibrosis with T2DM; male Sprague-Dawley albino rats were fed on a high-fat high-sucrose diet for 28 days then exposed to a single dose of STZ (30 mg/kg, IP). After two days of STZ injection, a diabetes confirmation test was done and all diabetic rats were constantly fed on HFD for thirty days with or without treatment with linagliptin (6 mg/kg). Hepatotoxicity markers, lipid profile screening, insulin signaling, inflammatory cytokines (TNF-α, IL-6, NF-κB p65), fibrosis markers (Collagen, α-SMA, TGF-ß1) and histopathological studies including hematoxylin and eosin (H&E) as well Masson's trichrome stains were performed. In our preliminary study, linagliptin at a dose of 6 mg/kg was chosen as the optimum anti-diabetic dose in rats challenged with STZ. Linagliptin significantly improved insulin sensitivity and lipid profile and reduced inflammatory mediators, and collagen depositions in rats with liver fibrosis and T2DM. In conclusion, above and beyond its anti-diabetic effect, this study introduced linagliptin as a promising option for preventing the pathological progression of liver fibrosis associated with T2DM.

Hepatoprotective Effect of Cranberry Nutraceutical Extract in Non-alcoholic Fatty Liver Model in Rats: Impact on Insulin Resistance and Nrf-2 Expression.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a pathological accumulation of triglycerides (TGs) in the hepatocyte in the absence of alcohol intake. Untreated NAFLD is expected to progress into liver fibrosis. Cranberry is rich in polyphenols with antioxidant and anti-inflammatory activities. HYPOTHESIS: The present study was performed to evaluate our hypothesis of the possible anti-fibrotic effect of cranberry nutraceuticals in a high fat cholesterol diet induced (HFCD)-NAFLD in rats, focusing on improving insulin sensitivity and modulating the expression of nuclear factor erythroid-2-related factor-2 (Nrf2) (a transcription factor responsible for regulating cellular redox balance). METHOD: Male albino wistar rats (12 weeks) received HFCD and/or cranberry (50 and 100 mg/kg/day, three times/week) orally for 8 consecutive weeks. RESULTS: In comparison to the HFCD group, cranberry treated groups (50 and 100 mg/kg) showed marked hepatoprotection, where it significantly decreased liver enzymes (alanine transaminases by 49 and 64% and aspartate transaminases by 45 and 64%; respectively), TGs, and ameliorated the histopathological alterations (such as inflammatory cells infiltration and ballooning degeneration) induced by HFCD. Cranberry also alleviated oxidative stress (malondialdehyde, glutathione, catalase and superoxide dismutase) and inflammation (tumor necrosis factor- alpha, interleukine-6 and nuclear factor kappa-b) and significantly reduced the HOMA-IR and TyG index. On the other hand, cranberry treated groups (50 and 100 mg/kg) showed a marked increase in the expression of adiponectin, by 8 and 13-fold, insulin receptor substrate-2 by 21 and 79%, and Nrf2 by 13 and 61%, respectively. Notably, cranberry significantly reduced the fibrotic markers, TGF-ß and α-SMA expression and collagen deposition. CONCLUSION: The present study showed that cranberry significantly attenuated NAFLD, in a dose dependent manner, which could be partially recognized by its antioxidant, anti-inflammatory activities, and its ability to improve insulin sensitivity. Notably, our study proves for the first time that the anti-fibrotic activity of cranberry is promising.

The angiotensin converting enzyme inhibitor captopril attenuates testosterone-induced benign prostatic hyperplasia in rats; a mechanistic approach.

Benign prostatic hyperplasia (BPH) is the most widespread urological disorder among elderly men. It is influenced by several factors, among which is the prostatic renin angiotensin system (RAS). Prostatic RAS activates several signaling pathways as proliferation, inflammation and angiogenesis that contribute to BPH development and progression. Captopril is a potent inhibitor of the angiotensin converting enzyme. Therefore, this study was performed to explore the potential protective effect of captopril against testosterone-induced BPH in rats. Male Sprague-Dawley rats were treated with either testosterone (3 mg/kg, s. c.) and/or captopril (100 mg/kg, orally) for four weeks. After treatments, prostatic serum markers and histopathology were assessed. Mechanistically, apoptotic, inflammatory and angiogenic pathways were examined. Testosterone significantly increased prostate weight, prostatic index, prostatic acid phosphatase and prostate specific antigen. These effects were almost prevented by captopril (100 mg/kg). Moreover, testosterone significantly elevated proliferating cell nuclear antigen and reduced Bax/Bcl-2 ratio, p53 and caspase-3 activity. Furthermore, it significantly elevated nuclear factor kappa-B, cyclooxygenase-II, tumor necrosis factor-α and interleukin-8. Besides, it caused a significant rise in vascular endothelial growth factor, basic fibroblast growth factor and matrix metalloproteinase-9. On the contrary, captopril effectively neutralised the proliferative, inflammatory and angiogenic effects of testosterone. Finally, the angiotensin-1 receptor expression in the BPH group was markedly decreased while captopril restored the receptor expression. Collectively, these findings indicate that captopril possesses a potent protective effect against testosterone-induced BPH via inducing apoptotic and suppressing inflammatory and angiogenic signaling pathways.