Genistein mitigates nitroglycerine-induced migraine: modulation of nitric oxide-mediated vasodilation and oxidative stress.

Migraine is a widespread brain condition described by frequent, recurrent episodes of incapacitating, moderate-to-severe headaches with throbbing pain that are usually one-sided. It is the 2nd most debilitating state lived with disability in terms of years, with a prevalence rate of 15-20%. Significant drops in estrogen levels have been associated with triggering acute migraine attacks in certain cases. Phytoestrogens are plant-derived compounds that resemble estrogen in structure, enabling them to imitate estrogen's functions in the body by attaching to estrogen receptors. Thus, the study was aimed to explore the protective effect of genistein against migraine. Moreover, the role of nitric oxide was also studied in the observed effect of genistein. Nitric oxide (NO) is implicated in migraine pathophysiology due to its role in promoting cerebral vasodilation and modulation of pain perception. Exploring L-NAME, a nitric oxide synthase inhibitor in migraine research helps scientists better understand the role of NO in migraine. Nitroglycerine treatment significantly increased the facial-unilateral head pain and spontaneous pain, as evidenced by the increased number of head scratching and groomings. Nitroglycerine treatment also induced anxiogenic behavior in mice. A significant reduction in the number of entries in the light phase and open arm, respectively. Biochemical analysis indicated a significant increase in inflammatory and oxidative stress in the nitroglycerin group. A significant increase and decrease in brain TBARS and GSH were observed with nitroglycerine treatment, respectively. Moreover, nitroglycerine treatment has uplifted the serum TNF-α level. Genistein (20 mg/kg) significantly mitigated the facial-unilateral head pain, spontaneous pain, photophobia, and anxiety-like behavior induced by nitroglycerine. Biochemical analysis showed that genistein (20 mg/kg) significantly abrogated the nitroglycerine-induced lipid peroxidation and increased serum TNF-α level. Genistein treatment also upregulated the brain GSH level and downregulated the serum TNF-α level. The L-NAME-mediated alleviation of the protective effect of genistein might be attributed to the vasodilatory effect of L-NAME. Conclusively, it can be suggested that genistein might provide relief from migraine pain by inhibiting nitric oxide-mediated vasodilation and oxidative stress.

Glycitein prevents reserpine-induced depression and associated comorbidities in mice: modulation of lipid peroxidation and TNF-α levels.

Depression is a debilitating mood disorder affecting millions worldwide and continues to pose a significant global health burden. Due to the multifaceted nature of depression, the current treatment regimens are not up to mark in terms of their multitargeting potential and least side effect profile. Molecules within the isoflavone class demonstrate promising potential in alleviating depression and associated conditions, offering a multifaceted approach to manage mental health concerns. Therefore, the current study was designed to explore the potential of glycitein, an isoflavone in managing reserpine-induced depression and associated comorbidities in mice. Reserpine (0.5 mg/kg; i.p.) administration for the first 3 days induced depression and associated comorbidities as evidenced by increased immobility time in forced swim test (FST) and tail suspension test (TST), along with reduced locomotor activity in the open field test (OFT) and increased latency to reach the platform in the Morris water maze (MWM) test. Reserpine treatment also upregulated and downregulated the brain thiobarbituric acid reactive substance (TBARS) and glutathione (GSH) levels, respectively. Furthermore, reserpine administration also uplifted the level of TNF-α in the serum samples. Glycitein (3 mg/kg and 6 mg/kg; p.o.) treatment for 5 days prevented the depressive effect of reserpine. It also improved the spatial memory at both dose levels. Moreover, in biochemical analysis, glycitein also reduced the brain TBARS and serum tumor necrosis factor-alpha (TNF-α) levels. Whereas, no significant effect was seen on the brain GSH level. Glycitein (6 mg/kg) was found to be more effective than the 3 mg/kg dose of glycitein. Overall results delineate that glycitein has the potential to manage depression and impaired memory by inhibiting lipid peroxidation and inflammatory stress.

Neuroprotective potential of formononetin, a naturally occurring isoflavone phytoestrogen.

The increased prevalence of neurological illnesses is a burgeoning challenge to the public healthcare system and presents greater financial pressure. Formononetin, an O-methylated isoflavone, has gained a lot of attention due to its neuroprotective potential explored in several investigations. Formononetin is widely found in legumes and several types of clovers including Trifolium pratense L., Astragalus membranaceus, Sophora tomentosa, etc. Formononetin modulates various endogenous mediators to confer neuroprotection. It prevents RAGE activation that results in the inhibition of neuronal damage via downregulating the level of ROS and proinflammatory cytokines. Furthermore, formononetin also increases the expression of ADAM-10, which affects the pathology of neurodegenerative disease by lowering tau phosphorylation, maintaining synaptic plasticity, and boosting hippocampus neurogenesis. Besides these, formononetin also increases the expression of antioxidants, Nrf-2, PI3K, ApoJ, and LRP1. Whereas, reduces the expression of p65-NF-κB and proinflammatory cytokines. It also inhibits the deposition of Aß and MAO-B activity. An inhibition of Aß/RAGE-induced activation of MAPK and NOX governs the protection elicited by formononetin against inflammatory and oxidative stress-induced neuronal damage. Besides this, PI3K/Akt and ER-α-mediated activation of ADAM10, ApoJ/LRP1-mediated clearance of Aß, and MAO-B inhibition-mediated preservation of dopaminergic neurons integrity are the major modulations produced by formononetin. This review covers the biosynthesis of formononetin and key molecular pathways modulated by formononetin to confer neuroprotection.

Signaling Pathways Involved in the Neuroprotective Effect of Osthole: Evidence and Mechanisms.

Neurodegenerative diseases constitute a major threat to human health and are usually accompanied by progressive structural and functional loss of neurons. Abnormalities in synaptic plasticity are involved in neurodegenerative disorders. Aberrant cell signaling cascades play a predominant role in the initiation, progress as well as in the severity of these ailments. Notch signaling is a pivotal role in the maintenance of neural stem cells and also participates in neurogenesis. PI3k/Akt cascade regulates different biological processes including cell proliferation, apoptosis, and metabolism. It regulates neurotoxicity and mediates the survival of neurons. Moreover, the activated BDNF/TrkB cascade is involved in promoting the transcription of genes responsible for cell survival and neurogenesis. Despite significant progress made in delineating the underlying pathological mechanisms involved and derangements in cellular metabolic promenades implicated in these diseases, satisfactory strategies for the clinical management of these ailments are yet to be achieved. Therefore, the molecules targeting these cell signaling cascades may emerge as useful leads in developing newer management strategies. Osthole is an important ingredient of traditional Chinese medicinal plants, often found in various plants of the Apiaceae family and has been observed to target these aforementioned mediators. Until now, no review has been aimed to discuss the possible molecular signaling cascades involved in osthole-mediated neuroprotection at one platform. The current review aimed to explore the interplay of various mediators and the modulation of the different molecular signaling cascades in osthole-mediated neuroprotection. This review could open new insights into research involving diseases of neuronal origin, especially the effect on neurodegeneration, neurogenesis, and synaptic plasticity. The articles gathered to compose the current review were extracted by using the PubMed, Scopus, Science Direct, and Web of Science databases. A methodical approach was used to integrate and discuss all published original reports describing the modulation of different mediators by osthole to confer neuroprotection at one platform to provide possible molecular pathways. Based on the inclusion and exclusion criteria, 32 articles were included in the systematic review. Moreover, literature evidence was also used to construct the biosynthetic pathway of osthole. The current review reveals that osthole promotes neurogenesis and neuronal functioning via stimulation of Notch, BDNF/Trk, and P13k/Akt signaling pathways. It upregulates the expression of various proteins, such as BDNF, TrkB, CREB, Nrf-2, P13k, and Akt. Activation of Wnt by osthole, in turn, regulates downstream GSK-1ß to inhibit tau phosphorylation and ß-catenin degradation to prevent neuronal apoptosis. The activation of Wnt and inhibition of oxidative stress, Aß, and GSK-3ß mediated ß-catenin degradation by osthole might also be involved in mediating the protection against neurodegenerative diseases. Furthermore, it also inhibits neuroinflammation by suppressing MAPK/NF-κB-mediated transcription of genes involved in the generation of inflammatory cytokines and NLRP-3 inflammasomes. This review delineates the various underlying signaling pathways involved in mediating the neuroprotective effect of osthole. Modulation of Notch, BDNF/Trk, MAPK/NF-κB, and P13k/Akt signaling pathways by osthole confers protection against neurodegenerative diseases. The preclinical effects of osthole suggest that it could be a valuable molecule in inspiring the development of new drugs for the management of neurodegenerative diseases and demands clinical studies to explore its potential. An effort has been made to unify the varied mechanisms and target sites involved in the neuroprotective effect of osthole. The comprehensive description of the molecular pathways in the present work reflects its originality and thoroughness. The reviewed literature findings may be extrapolated to suggest the role of othole as a "biological response modifier" which contributes to neuroprotection through kinase modulatory, immunomodulatory, and anti-oxidative activity, which is documented even at lower doses. The current review attempts to emphasize the gaps in the existing literature which can be explored in the future.

Neuroprotective potential of biochanin-A and review of the molecular mechanisms involved.

Biochanin-A is a naturally occurring plant phytoestrogen, which mimics specific the agonistic activity of estrogens. Biochanin-A is known to possess numerous activities, including neuroprotective, anti-diabetic, hepatoprotective, anti-inflammatory, antioxidant, and antimicrobial activities, along with the anticancer activity. Neuroinflammation is thought to play a pivotal pathological role in neurodegenerative disease. Sustained neuroinflammatory processes lead to progressive neuronal damage in Parkinson's and Alzheimer's disease. Activation of PI3K/Akt cascade and inhibition of MAPK signaling cascade have been observed to be responsible for conferring protection against neuroinflammation in neurodegenerative diseases. An increased oxidative stress promotes neuronal apoptosis via potentiating the TLR-4/NF-κB and inhibiting PI3K/Akt signaling mediated increase in pro-apoptotic and decreases in antiapoptotic proteins. Various authors have explored biochanin-A's neuroprotective effect by using various cell lines and animal models. Biochanin-A has been reported to mediate its neuroprotective via reducing the level of oxidants, inflammatory mediators, MAPK, TLR-4, NF-κB, NADPH oxidase, AchE, COX-2 and iNOS. Whereas, it has been observed to increase the level of anti-oxidants, along with phosphorylation of PI3K and Akt proteins. The current review has been designed to provide insights into the neuroprotective effect of biochanin-A and possible signaling pathways leading to protection against neuroinflammation and apoptosis in the central nervous system. This review will be helpful in guiding future researchers to further explore biochanin A at a mechanistic level to obtain useful lead molecules.

Exploring the possible mechanism involved in the anti-nociceptive effect of ß-sitosterol: modulation of oxidative stress, nitric oxide and IL-6.

Β-sitosterol is a phytosterol, documented to possess various activities including protection against inflammation, diabetes and Alzheimer's disease. The current investigation was designed to explore the analgesic potential of ß-sitosterol and the possible molecular mechanism involved in the observed effect. ß-sitosterol was administered at varying doses of 10, 20, and 40 mg/kg before subjecting the mice to acetic acid and formalin challenges. The number of writhings in acetic acid and the number of flinchings and foot tappings were quantified in the formalin test. For mechanistic studies, substance P (cyclooxygenase-2 (COX-2) stimulator) and L-Nitro arginine methyl ester (L-NAME) (nitric oxide synthetases (NOS) inhibitor) and L-arginine (nitric oxide precursor) were administered before ß-sitosterol treatment. ß-sitosterol (10, 20, 40 mg/kg) treatment significantly reduced acetic acid-induced writhings and ameliorated the formalin-induced inflammatory phase dose-dependently. Whereas, 40 mg/kg dose of ß-sitosterol abrogated the formalin-induced neurogenic phase. Substance-P abrogated the effect of ß-sitosterol in both neurogenic and inflammatory phases. Whereas, L-arginine only abrogated the inflammatory phase. In biochemical analysis, ß-sitosterol treatment reduced the level of interleukin-6 (IL-6), thiobarbituric acid reactive substances (TBARS) and increased the level of reduced glutathione (GSH). Furthermore, L-arginine and substance-P abrogated the GSH increasing and TBARS lowering effect of ß-sitosterol (40 mg/kg). Overall, the current study delineated that ß-sitosterol may induce an anti-nociceptive effect via inhibiting the IL-6, oxidative stress, cyclo-oxygenase and nitric oxide.

Prognostic Nutritional Index Prior to Rectal Cancer Resection Predicts Overall Survival.

Prognostic nutritional index (PNI) correlates with postoperative complications and survival in colorectal cancers. Separate studies for rectal cancers are not available where the majority have preoperative radiation, operated by minimally invasive approaches and have diverting ostomies.Consecutive rectal resections between October 2014 and December 2017 from a single center were included. PNI was calculated as 10 x (serum Albumin) + 0.005 x TLC (per mm3) before operation. Multivariate cox regression was used with overall survival (OS) as the dependent variable. Interaction terms of PNI with neoadjuvant therapy, surgical approach and postoperative complications were used to assess specific subgroups.Three-hundred forty elective rectal resections were included with a mean PNI of 46.711 (SD - 6.692), and a median follow up of 44 mo. In multivariable regression, PNI predicted OS (HR - 0.943; p-0.001). Interaction of PNI with preoperative radiation or surgical approach (open, laparoscopic, or robotic) did not change its influence on survival. PNI predicted survival with similar hazard even in patients without major postoperative complicationsDespite routine diversion after rectal resections, PNI predicted OS with an absolute survival benefit of 1.2% at 3-year for every unit increase in PNI irrespective of preoperative therapy or surgical approach.

Mechanistic interplay of various mediators involved in mediating the neuroprotective effect of daphnetin.

Daphnetin is a 7, 8 dihydroxy coumarin isolated from different medicinal plants of the Thymelaeaceae family and exhibits copious pharmacological activities including neuroprotection, anti-cancer, anti-malarial, anti-inflammatory, anti-parasitic and anti-arthritic activity. It has been proved to be an effective neuroprotective agent in several preclinical animal studies and cell line examinations. It is found to interact with different cellular mediators and signaling pathways to confer protection against neurodegeneration. The reactive oxygen species and inflammatory mediators are the major culprits of different neurodegenerative diseases. Oxidative stress activates the pro-apoptotic proteins and inhibits anti-apoptotic proteins, leading to neuronal cell death. Daphnetin restores cellular redox balance by upregulating the antioxidants level (GSH and SOD), anti-apoptotic protein (Bcl-2), as well as by reducing the levels of proinflammatory cytokines, executioner caspase-3, pro-apoptotic-Bax, and oxidative stress markers. Furthermore, activation of Nrf-2/HO-1 signaling and upregulation of HSP-70 governs the protection elicited by daphnetin against oxidative stress-induced neuronal apoptosis. Daphnetin modulated inhibition of JNK-MAPK, JAK-STAT, and TLR-4/NF-κB signaling pathways also contributed to its neuroprotective effect. The positive effects of daphnetin have been also related to its AChE, BChE, and BACE-1 inhibitory potential. The present review has been designed to explore the mechanistic interplay of various mediators in mediating the neuroprotective effects of daphnetin.

Daphnetin, a natural coumarin averts reserpine-induced fibromyalgia in mice: modulation of MAO-A.

Fibromyalgia is a common, chronic, and generalized pain syndrome that is often associated with comorbid depression. The etiology of fibromyalgia is complex; most researchers have documented that the hallmark symptoms are due to the central nervous system's abnormal functioning. Neurotransmitters such as serotonin, norepinephrine, and glutamate, have been reported to be key regulators of fibromyalgia syndrome. Daphnetin is a 7, 8 dihydroxy coumarin widely distributed in Thymelaeaceae family plants, possessing various activities such as anti-arthritic, anti-tumor, anti-malarial, and anti-parasitic. The present study was designed to explore the potential of daphnetin against reserpine-induced fibromyalgia in mice. In mice, a fibromyalgia-like state was achieved by injecting reserpine (0.5 mg/kg, s.c) continuously for 3 days. All behavioral tests were conducted on the 4th and 6th day of experimentation. Reserpine administration significantly increased the mechanical hypersensitivity in electronic von Frey (eVF) and pressure application measurement (PAM) tests. It also increased the immobility period and time to reach the platform in force swim test (FST) and Morris water maze (MWM) test, respectively. In the biochemical analysis, reserpine treatment upregulated the monoamine oxidase-A (MAO-A) activity and level of glutamate, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), and thiobarbituric acid reactive substances (TBARS). Whereas, it decreased the level of glutathione (GSH), dopamine, serotonin, and norepinephrine. Daphnetin pretreatment attenuated the behavioral and biochemical changes induced by reserpine. Thus, the current investigation results delineate that daphnetin might exert its protective effect by inhibiting inflammatory stress and MAO-A-mediated neurotransmitter depletion and oxidative stress.

Compliance and perception about personal protective equipment among health care workers involved in the surgery of COVID-19 negative cancer patients during the pandemic.

BACKGROUND: Health care workers (HCWs) are at risk of getting infected while at work, for example, operating room (OR), hence it is pertinent that they don all the appropriate personal protective equipment (PPE) to minimize the chance of getting infected. METHODS: A COVID-19 specific briefing and debriefing form was created and used in the OR along with the World Health Organization surgical safety checklist to reinforce the use of appropriate PPE. An audit was subsequently done to understand the compliance to PPE use, followed by a survey based on the findings of the audit to understand the issues related to noncompliance. RESULTS: The form was used in 183 out of the 238 (77%) surgeries performed during a months' time. The overall compliance for PPE usage was 96.3%. Noncompliance was seen most often for eye protection (45/567) (P = .01). The survey revealed that this was mostly among surgeons mainly due to discomfort, poor visibility, and frequent fogging. CONCLUSIONS: Our HCW were adapting well to the new normal of donning appropriate PPE in the OR, except for the eye protection due to discomfort and visibility related issues. This is important to know so that necessary changes could be introduced to better the compliance.

Protective Effect of Esculetin, Natural Coumarin in Mice Model of Fibromyalgia: Targeting Pro-Inflammatory Cytokines and MAO-A.

Fibromyalgia is a refractory syndrome characterized by chronic wayward pain and complex co-morbid psychological trepidation. The current treatments have a limited role and proper clinical benefits are far from satisfactory. Naturally occurring coumarins such as osthole are known to have analgesic and anti-inflammatory activities. Therefore, the current investigation was designed to explore the potential of natural coumarin esculetin (2.5, 5, and 10 mg/kg) in mitigating reserpine-induced fibromyalgia in Swiss albino mice. Esculetin is a 6,7 dihydroxy-coumarin obtained from various plant sources such as Aesculus hippocastanum L, Ceratostigma willmottianum, Citrus limonia, etc. Reserpine (0.5 mg/kg/day s.c.) treatment for first 3 days, significantly altered the behavior of mice as evidenced by reduced paw withdrawal threshold in pressure application measurement (PAM) test and electronic von-Frey (eVF) test, increased immobility time in forced swim test (FST), increased latency to reach the platform in Morris water maze (MWM) test and reduced number of square crossed in the open field test (OFT). These behavioral deficits with reserpine treatment were integrated with a reduced level of serotonin (5-HT), reduced glutathione (GSH), along with an increase in monoamine oxidase-A (MAO-A) activity, pro-inflammatory cytokines (IL-1ß, TNF-α), thiobarbituric acid reactive substances (TBARS) and glutamate level. Esculetin (10 mg/kg/day i.p) treatment for 5 days, significantly abrogated reserpine induced behavioral and biochemical alterations. Whereas, no significant improvement was observed with lower doses of esculetin i.e. 2.5 and 5 mg/kg.

Ameliorative effect of imperatorin in chemically induced fibromyalgia: Role of NMDA/NFkB mediated downstream signaling.

Fibromyalgia (FM) is a chronic pain syndrome involving complex interplay of biogenic amines and NMDA receptor mediated hypersensitization of nociceptive pathways. Clinical management of FM is poorly addressed with only a few available therapeutic options. Coumarins are active phenolic molecules of natural origin found to have broad pharmacological activities. Current investigation explores the role of naturally occurring coumarin, imperatorin in mouse model of fibromyalgia. Administration of reserpine (0.5 mg/kg, s.c.) thrice at 24 h intervals induced behavioral and neurochemical alterations characteristic of fibromyalgia. Reserpine was found to induce allodynia quantified using electronic von Frey (e-VF) and pressure application measurement (PAM) test, depression as indicated by an increased duration of immobility in forced swim test (FST), decreased motor coordination and locomotor activity in inclined plane test (IPT) and open field test (OFT) respectively. Cognitive deficits were evident by an increased latency to locate hidden platform in Morris water maze (MWM) and passive avoidance test (PAT). Reserpine treatment was found to cause an increased anxiety as revealed by increased time spent in closed arm of the elevated plus maze (EPM). Furthermore, an up- regulation in NMDA and NFκB expression in the brain and spinal cord was observed in reserpine treated groups. Administration of imperatorin (10 mg/kg, i.p) for a period of 5 days ameliorated all behavioral deficits, biochemical changes and decreased expression of NMDA and NFκB in the brain and spinal cord of treated mice. These findings indicate an interplay of NMDA/NFκB modulation by imperatorin in the reserpine induced fibromyalgia in mice.

Possible Molecular Mediators Involved and Mechanistic Insight into Fibromyalgia and Associated Co-morbidities.

Fibromyalgia is a chronic complex syndrome of non-articulate origin characterized by musculoskeletal pain, painful tender points, sleep problems and co-morbidities including depression, migraine. The etiopathogenesis of fibromyalgia is complex, variable and remains inconclusive. The etiological factors that have been defined include stress, genetic predisposition and environmental components. As per the reports of the American College of Rheumatology (ACR) the prevalence of fibromyalgia varies from 2 to 22% among the general population with poor diagnostic features primarily pain. Fibromyalgia encompasses a spectrum of co-morbid conditions with multifarious pathogenesis. The highly prevalent manifestations of fibromyalgia include heterogeneous pain and aches. Biochemical and neurobiological elements of fibromyalgia include neurotransmitters, hypothalamic pituitary adrenal axis (HPA axis), inflammatory cytokines, monoaminergic pathway, opioid peptides, sex hormones, nerve growth factor (NGF) and local free radical insult. An imbalance in the serotonergic system is the major underlying etiological factor that has been explored most widely. Owing to complex interplay of diverse pathophysiological pathways, overlapping co-morbidities such as depression have been clinically observed. Therapeutic management of fibromyalgia involves both non pharmacological and pharmacological measures. The current review presents various dysregulations and their association with symptoms of fibromyalgia along with their underlying neurobiological aspects.

Mechanisms involved in adenosine pharmacological preconditioning-induced cardioprotection.

Adenosine is a naturally occurring breakdown product of adenosine triphosphate and plays an important role in different physiological and pathological conditions. Adenosine also serves as an important trigger in ischemic and remote preconditioning and its release may impart cardioprotection. Exogenous administration of adenosine in the form of adenosine preconditioning may also protect heart from ischemia-reperfusion injury. Endogenous release of adenosine during ischemic/remote preconditioning or exogenous adenosine during pharmacological preconditioning activates adenosine receptors to activate plethora of mechanisms, which either independently or in association with one another may confer cardioprotection during ischemia-reperfusion injury. These mechanisms include activation of KATP channels, an increase in the levels of antioxidant enzymes, functional interaction with opioid receptors; increase in nitric oxide production; decrease in inflammation; activation of transient receptor potential vanilloid (TRPV) channels; activation of kinases such as protein kinase B (Akt), protein kinase C, tyrosine kinase, mitogen activated protein (MAP) kinases such as ERK 1/2, p38 MAP kinases and MAP kinase kinase (MEK 1) MMP. The present review discusses the role and mechanisms involved in adenosine preconditioning-induced cardioprotection.

Investigating the possible mechanisms involved in adenosine preconditioning-induced cardioprotection in rats.

BACKGROUND: Adenosine is a breakdown product of adenosine triphosphate and plays an important role in pharmacological preconditioning. The cardioprotective effects of adenosine preconditioning are well established. However, the possible mechanisms need to be explored. AIM: This study was aimed to investigate the possible mechanisms involved in adenosine preconditioning-induced cardioprotection in rats. METHODS: Rat heart was isolated and perfused on Langendorff apparatus. Global ischemia for 30 minutes followed by reperfusion for 120 minutes was employed to produce myocardial injury. Myocardial injury was assessed by measuring myocardial infarct size, release of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary effluent and hemodynamic parameters including left ventricular developed pressure (LVDP), dp/dtmax, and dp/dtmin . Serum nitrite levels were measured as an index of nitric oxide release in blood. RESULTS: Adenosine (4 mg/kg) preconditioning significantly decreased ischemia-reperfusion-induced increase in LDH, CK release, infarct size, improved LVDP, dp/dtmax and dp/dtmin, and increased serum nitrite levels. Pretreatment with L-NAME, a specific NOS inhibitor, (5 mg/kg) and montelukast, leukotriene receptor antagonist, (10 mg/kg) significantly abrogated the cardioprotective effect of adenosine preconditioning. However, seratrodast, thromboxane A2 antagonist, (15 mg/kg) had no effect on adenosine-induced cardioprotection. Sodium nitroprusside (SNP) preconditioning also produced cardioprotective effects. However, caffeine (20 mg/kg) (adenosine receptor blocker) and seratrodast (15 mg/kg) had no effect on SNP-induced cardioprotection. Administration of montelukast abrogated the cardioprotective effects of SNP preconditioning-induced cardioprotection. CONCLUSION: Adenosine preconditioning may increase the release of nitric oxide, which in turn may increase the release of cysteinyl leukotrienes to confer cardioprotection.