Vinpocetine and Ischemic Stroke

Vinpocetine (VPN) is a synthetic ethyl-ester derivative of the alkaloid apovincamine from Vinca minor leaves. VPN is a selective inhibitor of phosphodiesterase type 1 (PDE1) has potential neurological effects through inhibition of voltage gated sodium channel and reduction of neuronal calcium influx. VPN have noteworthy antioxidant, anti-inflammatory and anti-apoptotic effects with inhibitory effect on glial and astrocyte cells during and following ischemic stroke (IS). VPN is effective as an adjuvant therapy in the management of epilepsy; it reduces seizure frequency by 50% in a dose of 2 mg/kg/day. VPN improves psychomotor performances through modulation of brain monoamine pathway mainly on dopamine and serotonin, which play an integral role in attenuation of depressive symptoms. VPN recover cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE-1with augmentation of cAMP/cGMP ratio, enhancement of cholinergic neurotransmission and inhibition of neuronal inflammatory mediators. Therefore, VPN is an effective agent in the management of ischemic stroke and plays an integral role in the prevention and attenuation of post-stroke epilepsy, depression and cognitive deficit through direct cAMP/cGMP-dependent pathway or indirectly through anti-inflammatory and anti-oxidant effects

Orexin and Psychoneurobiology: A Hidden Treasure

Orexin is a neuropeptide secreted from the lateral hypothalamus and prefrontal cortex concerned in wakefulness and excitement. This study aimed to review the possible neurobiological effect of orexin. A diversity of search strategies was adopted and assumed which included electronic database searches of Medline and PubMed using MeSH terms, keywords, and title words. Orexin plays a vital role in activation of learning, memory acquisition, and consolidation through activation of the monoaminergic system, which affects cognitive flexibility and cognitive function. Orexin stimulates adrenocorticotrophin (ACTH) and corticosteroid secretions via activation of the central corticotropin-releasing hormone (CRH). Cerebrospinal (CSF) and serum orexin serum levels are reduced in depression, schizophrenia, and narcolepsy. However, high orexin serum levels are revealed in drug addictions. Regarding neurodegenerative brain diseases, CSF and serum orexin levels are reduced in Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Orexin antagonist leads to significant reduction of sympathetic overactivity during withdrawal syndrome. Also, orexin antagonist improves sleep pattern. The orexinergic system is involved in different psychiatric and neurological disorders; therefore targeting of this system could be a possible novel pathway in the management of these disorders. In addition measurement of CSF and serum orexin levels might predict the relapse and withdrawal of addict patients

BETTERMENT OF DICLOFENAC-INDUCED NEPHROTOXICITY BY PENTOXIFYLLINE THROUGH MODULATION OF INFLAMMATORY BIOMARKERS

Objectives: Diclofenac-induced nephrotoxicity is caused by oxidative stress which leads to lipid peroxidation and formation of free radicals. Pentoxifylline can ameliorates renal tissue injury by its anti-inflammatory, antifibrotic, and antioxidant effects, so it mitigates the progression of renal diseases. Therefore, the aim of this study was to evaluate the nephroprotective effects of pentoxifylline on diclofenac-induced nephrotoxicity in rats. Methods: A total of 30 male Sprague-Dawley rats were allocated into three groups, Group 1 (n=10): Rats treated with distilled water 5 ml/kg plus normal saline 5 ml/kg for 12 days, Group 2 (n=10): Rats treated with distilled water 5 ml/kg plus diclofenac 15 mg/kg for 12 days, and Group 3 (n=10): Rats treated with pentoxifylline 100 mg/kg plus diclofenac 15 mg/kg for 12 days. Blood urea, creatinine, malondialdehyde (MDA), superoxide dismutase (SOD-1), glutathione reductase (GSH), neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecules (KIM-1) vitronectin (VTN), integrin (ITG) , interleukin-18 (IL-18) and cystatin-C were used to measure the severity of nephrotoxicity. Results: Diclofenac-induced nephrotoxicity led to significant elevation in blood urea, serum creatinine, MDA, IL-18, KIM-1, NGAL, serum ITG, and VTN with decrease of SOD-1 and GSH sera levels p<0.05. Treatment with pentoxifylline showed no significant effect on all biomarker levels compared to diclofenac group except on serum level KIM-1 and serum VTN, p<0.05. Conclusion: Pentoxifylline produced significant nephroprotective effect on diclofenac-induced nephrotoxicity through modulation of inflammatory biomarkers

FEBUXOSTAT MODULATES OXIDATIVE AND APOPTOTIC PATHWAYS IN ACUTE DOXORUBICIN‑INDUCED CARDIOTOXICITY: AN EXPERIMENTAL ANIMAL MODEL STUDY

Objectives: Doxorubicin is one of the most important and powerful anticancer drugs, the most pronounced limitation for its use is toxicity on normal cells. Mechanism of doxorubicin-induced cardiotoxicity (DIC) is multifactorial and complex, including direct DNA damage, formation of free radicals, interference with DNA repair, and activation of immune reactions. Febuxostat is a non-purine-selective xanthine oxidase inhibitor decrease the production of uric acid. The aim of the present study was to evaluate the influence of febuxostat on doxorubicin-induced acute cardiotoxicity in rats regarding oxidative stress and antiapoptotic effects. Methods: A total of 30 Sprague Dawley male rats were used which subdivided into three groups: Group I (negative control group) received normal saline for 10 days, Group II (positive control group) received normal saline plus single dose of doxorubicin (15 mg/kg, IP), and Group III (treated group) received febuxostat (10 mg/kg, po), for 10 successive days plus single dose of doxorubicin (15 mg/kg, I.P.). Serum brain natriuretic peptide (BNP), cardiac troponin I (cTn-I), caspase-3, glutathione peroxidase (GSH-Px), lipid peroxidase (LPO), malondialdehyde (MDA), and tumor necrosis factor alpha were estimated by ELISA kit method. Results: Febuxostat administration before doxorubicin led to significant decrease on cardiac troponin, caspase-3, and elevation in GSH-Px levels significantly p<0.05. While the effects of febuxostat on BNP, LPO, MDA, tumor necrosis-alpha were insignificant p>0.05 compare to doxorubicin. Conclusion: Febuxostat attenuates DIC through modulation of antioxidant, anti-inflammatory, and antiapoptotic biomarkers

ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS OF CURCUMIN CONTRIBUTE INTO ATTENUATION OF ACUTE GENTAMICIN-INDUCED NEPHROTOXICITY IN RATS

Objectives: Nephrotoxicity is a renal-specific situation in which the excretion of toxic metabolites is reduced due to toxic agents and drugs. Gentamicin is an antibiotic belongs to aminoglycoside group which may induce nephrotoxicity due to induction of oxidative stress. Curcumin is a component of traditional medicine with significant nephroprotective effect. Therefore, the objective of the present study was to evaluate the nephroprotective effect of curcumin on gentamicin-induced nephrotoxicity. Methods: A total of 30 male Sprague-Dawley rats were used which divided into Group 1 (n=10): Rats treated with distilled water 5 ml/kg plus normal saline 5 ml/kg for 12 days, Group 2 (n=10): Rats treated with distilled water 5 ml/kg plus gentamicin 100 mg/kg for 12 days, and Group 3 (n=10): Rats treated with curcumin 100 mg/kg plus gentamicin 100 mg/kg for 12 days. Blood urea, serum creatinine, malondialdehyde (MDA), kidney injury molecule (KIM-1), and cystatin-C were measured in both control and experimental groups. Results: Rats treated with gentamicin showed nephrotoxicity as evident by significant elevation in blood urea, serum creatinine, KIM-1, MDA, and cystatin-C sera levels. Curcumin leads to significant reduction of blood urea and serum creatinine compared to gentamicin group, p<0.05. Curcumin also reduced MDA, KIM-1, and cystatin-C sera levels significantly compared to gentamicin group, p<0.01. Conclusion: Curcumin produced significant nephroprotective effect on gentamicin-induced nephrotoxicity through modulation of oxidative stress and inflammatory biomarkers

POMEGRANATE ATTENUATES ACUTE GENTAMICIN-INDUCED NEPHROTOXICITY IN SPRAGUE-DAWLEY RATS: THE POTENTIAL ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS

Objectives: Nephrotoxicity is a renal-specific situation in which the excretion of toxic metabolites is reduced due to toxic agents and drugs. Gentamicin is an antibiotic belongs to aminoglycoside group which may induce nephrotoxicity due to induction of oxidative stress. Pomegranate is a component of the traditional medicine called Punica granatum with significant nephron-protective effect. Therefore, the objective of the present study was to evaluate the nephronprotective effect of pomegranate in gentamicin-induced nephrotoxicity. Methods: A total of 30 male Sprague-Dawley rats were used which divided into Group 1 (n=10): Rats treated with distilled water 5 ml/kg plus normal saline 5 ml/kg for 12 days, Group 2 (n=10): Rats treated with distilled water 5 ml/kg plus gentamicin 100 mg/kg for 12 days, and Group 3 (n=10): Rats treated with pomegranate 100 mg/kg plus gentamicin 100 mg/kg for 12 days. Blood urea, serum creatinine, malondialdehyde (MDA), kidney injury molecule (KIM-1), and cystatin-C were measured in both control and experimental groups. Results: Rats treated with gentamicin showed nephrotoxicity as evident by significant elevation in serum creatinine, blood urea, serum creatinine, KIM-1, MDA, and cystatin-C sera levels. Pomegranate leads to significant reduction of blood urea and serum creatinine compared to gentamicin group, p<0.05. Pomegranate also reduced MDA, KIM-1, and cystatin-C sera levels significantly compared to gentamicin group, p<0.01. Conclusion: Pomegranate produced significant nephroprotective effect on gentamicin-induced nephrotoxicity through modulation of oxidative stress and inflammatory biomarkers

Pirfenidone and post-Covid-19 pulmonary fibrosis: invoked again for realistic goals

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGPirfenidone (PFN) is an anti-fbrotic drug with signifcant anti-infammatory property used for treatment of fbrotic conditions such as idiopathic pulmonary fbrosis (IPF). In the coronavirus disease 2019 (Covid-19) era, severe acute respiratory syndrome 2 (SARS-CoV-2) could initially lead to acute lung injury (ALI) and in severe cases may cause acute respiratory distress syndrome (ARDS) which is usually resolved with normal lung function. However, some cases of ALI and ARDS are progressed to the more severe critical stage of pulmonary fbrosis commonly named post-Covid-19 pulmonary fbrosis which needs an urgent address and proper management. Therefore, the objective of the present study was to highlight the potential role of PFN in the management of post-Covid-19 pulmonary fbrosis. The precise mechanism of post-Covid-19 pulmonary fbrosis is related to the activation of transforming growth factor beta (TGF-β1), which activates the release of extracellular proteins, fbroblast proliferation, fbroblast migration and myofbroblast conversion. PFN inhibits accumulation and recruitment of infammatory cells, fbroblast proliferation, deposition of extracellular matrix in response to TGFβ1 and other pro-infammatory cytokines. In addition, PFN suppresses furin (TGFβ1 convertase activator) a protein efector involved in the entry of SARS-CoV-2 and activation of TGFβ1, and thus PFN reduces the pathogenesis of SARS-CoV-2. Besides, PFN modulates signaling pathways such as Wingless/Int (Wnt/β-catenin), Yes-Associated Protein (YAP)/Transcription CoActivator PDZ Binding Motif (TAZ) and Hippo Signaling Pathways that are involved in the pathogenesis of post-Covid-19 pulmonary fbrosis. In conclusion, the anti-infammatory and anti-fbrotic properties of PFN may attenuate post-Covid-19 pulmonary fbrosis

COVID-19 in relation to hyperglycemia and diabetes mellitus

Coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may lead to extrapulmonary manifestations like diabetes mellitus (DM) and hyperglycemia, both predicting a poor prognosis and an increased risk of death. SARS-CoV-2 infects the pancreas through angiotensin-converting enzyme 2 (ACE2), where it is highly expressed compared to other organs, leading to pancreatic damage with subsequent impairment of insulin secretion and development of hyperglycemia even in non-DM patients. Thus, this review aims to provide an overview of the potential link between COVID-19 and hyperglycemia as a risk factor for DM development in relation to DM pharmacotherapy. For that, a systematic search was done in the database of MEDLINE through Scopus, Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), and Wanfang Data. Data obtained underline that SARS-CoV-2 infection in DM patients is more severe and associated with poor clinical outcomes due to preexistence of comorbidities and inflammation disorders. SARS-CoV-2 infection impairs glucose homeostasis and metabolism in DM and non-DM patients due to cytokine storm (CS) development, downregulation of ACE2, and direct injury of pancreatic beta-cells. Therefore, the potent anti-inflammatory effect of diabetic pharmacotherapies such as metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors (SGLT2Is), and dipeptidyl peptidase-4 (DPP4) inhibitors may mitigate COVID-19 severity. In addition, some antidiabetic agents and also insulin may reduce SARS-CoV-2 infectivity and severity through the modulation of the ACE2 receptor expression. The findings presented here illustrate that insulin therapy might seem as more appropriate than other anti-DM pharmacotherapies in the management of COVID-19 patients with DM due to low risk of uncontrolled hyperglycemia and diabetic ketoacidosis (DKA). From these findings, we could not give the final conclusion about the efficacy of diabetic pharmacotherapy in COVID-19; thus, clinical trial and prospective studies are warranted to confirm this finding and concern

Fenofibrate for COVID-19 and related complications as an approach to improve treatment outcomes: the missed key for Holy Grail

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGIntroduction Fenofbrate is an agonist of peroxisome proliferator activated receptor alpha (PPAR-α), that possesses antiinfammatory, antioxidant, and anti-thrombotic properties. Fenofbrate is efective against a variety of viral infections and diferent infammatory disorders. Therefore, the aim of critical review was to overview the potential role of fenofbrate in the pathogenesis of SARS-CoV-2 and related complications. Results By destabilizing SARS-CoV-2 spike protein and preventing it from binding angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 entry, fenofbrate can reduce SARS-CoV-2 entry in human cells Fenofbrate also suppresses infammatory signaling pathways, which decreases SARS-CoV-2 infection-related infammatory alterations. In conclusion, fenofbrate anti-infammatory, antioxidant, and antithrombotic capabilities may help to minimize the infammatory and thrombotic consequences associated with SARSCoV-2 infection. Through attenuating the interaction between SARS-CoV-2 and ACE2, fenofbrate can directly reduce the risk of SARS-CoV-2 infection. Conclusions As a result, fenofbrate could be a potential treatment approach for COVID-19 control

The Potential Role of Renin Angiotensin System (RAS) and Dipeptidyl Peptidase-4 (DPP-4) in COVID-19: Navigating the Uncharted

Novel coronavirus (COVID-19) led to infected pneumonia and acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). The entry-point receptor for COVID-19 is angiotensin-converting enzyme 2 (ACE2) at lung, and dipeptidyl peptidase-4 (DPP-4) is a receptor for Middle East respiratory syndrome coronavirus (MERS-CoV). There is 80% similarity between MERS-CoV and COVID-19. This study was planned to review the potential link between the incidence and severity of COVID-19 regarding the modulation of DPP-4 and ACE2 by DPP-4 and renin angiotensin system (RAS). In COVID-19, SARS-CoV2 binds ACE2 which is highly expressed by the epithelial cells of the blood vessel, intestine, and lung. However, pulmonary ACE2 seems to be a protective defense pathway during ARDS. DPP-4 is not concerned with the entry of COVID-19 but mediates the inflammatory reactions and cytokine storm that induced ARDS and AKI by COVID-19. The interaction between DPP4i and RAS inhibitors seem to augment the expression of AT2 receptor and ACE2 which are under extensive researches to find the pathophysiological pathway of COVID-19 infection. This beneficial interaction between DPP4i and RAS shed light for possible attenuation of COVID-19-induced ARDS and AKI mainly in critically ill patients with systemic hypertension