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This study examines the effectiveness of lupeol and metformin in a mouse model of dementia generated by intracerebroventricular streptozotocin (i.c.v., STZ). Dementia was induced in Swiss mice with the i.c.v. administration of STZ at a dosage of 3 mg/kg on the first and third day. The assessment of dementia involved an examination of the Morris Water Maze (MWM) performance, as well as a number of biochemical and histological studies. STZ treatment resulted in significant decrease in MWM performance; various biochemical alterations (increase in brain acetyl cholinesterase (AChE) activity, thiobarbituric acid reactive species (TBARS), nitrite/nitrate, and reduction in nuclear factor erythroid 2 related factor-2 (Nrf-2), reduced glutathione (GSH) levels) and neuroinflammation [increased myeloperoxidase (MPO) activity & neutrophil infiltration]. The administration of Lupeol (50 mg/kg & 100 mg/kg; p.o.) and Metformin (150 mg/kg & 300 mg/kg; p.o.) demonstrated a considerable reduction in the behavioral, biochemical, and histological alterations produced by STZ. Low dose combination of lupeol (50 mg/kg; p.o.) and Metformin (150 mg/kg; p.o.) produced more pronounced effect than that of high doses of either agent alone. It is concluded that Lupeol and Metformin has shown efficacy in dementia with possible synergism between the two and can be explored as potential therapeutic agents for managing dementia of Alzheimer's disease (AD) type.

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OBJECTIVES: Noninvasive remote ischemic preconditioning (RIPC) is a practical, acceptable, and feasible conditioning technique reported to provide cardioprotection in myocardial ischemia-reperfusion injury (MIRI). It has been well-reported that quercetin possesses antioxidant and anti-inflammatory properties. This study investigates the modification of the cardioprotective response of RIPC by quercetin. METHODS: Adult Wistar rats were randomized into 12 groups of six animals each. MIRI was induced by subjecting the isolated hearts of Wistar rats to global ischemia for 30 min, succeeded by reperfusion of 120 min after mounting on the Langendorff PowerLab apparatus. Hind limb RIPC was applied in four alternate cycles of ischemia and reperfusion of 5 min each by tying the pressure cuff before isolation of hearts. RESULTS: MIRI was reflected by significantly increased infarct size, LDH-1, and CK-MB, TNF-α, TBARS, and decreased GSH, catalase, and hemodynamic index, and modulated Nrf2. Pretreatment of quercetin (25 and 50 mg/kg; i.p.) significantly attenuated the MIRI-induced cardiac damage and potentiated the cardioprotective response of RIPC at the low dose. Pretreatment of ketamine (10 mg/kg; i.p.), an mTOR-dependent autophagy inhibitor, significantly abolished the cardioprotective effects of quercetin and RIPC. CONCLUSIONS: The findings highlight the modification of the cardioprotective effect of RIPC by quercetin and that quercetin protects the heart against MIRI through multiple mechanisms, including mTOR-dependent activation of autophagy and Nrf-2 activation.

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Transient receptor potential vanilloid subfamily member 1 (TRPV1) has been strongly implicated in the pathophysiology of cerebral stroke. However, the exact role and mechanism remain elusive. TPRV1 channels are exclusively present in the neurovascular system and involve many neuronal processes. Numerous experimental investigations have demonstrated that TRPV1 channel blockers or the lack of TRPV1 channels may prevent harmful inflammatory responses during ischemia-reperfusion injury, hence conferring neuroprotection. However, TRPV1 agonists such as capsaicin and some other non-specific TRPV1 activators may induce transient/slight degree of TRPV1 channel activation to confer neuroprotection through a variety of mechanisms, including hypothermia induction, improving vascular functions, inducing autophagy, preventing neuronal death, improving memory deficits, and inhibiting inflammation. Another factor in capsaicin-mediated neuroprotection could be the desensitization of TRPV1 channels. Based on the summarized evidence, it may be plausible to suggest that TPRV1 channels have a dual role in ischemia-reperfusion-induced cerebral injury, and thus, both agonists and antagonists may produce neuroprotection depending upon the dose and duration. The current review summarizes the dual function of TRPV1 in ischemia-reperfusion-induced cerebral injury models, explains its mechanism, and predicts the future.

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Ephrins are protein ligands that act through the tyrosine kinase receptor family, Eph receptors. The role of ephrin/Eph in the critical processes involved in the development of the nervous system, including axon guidance and cell migration, has been well documented. Moreover, studies have shown an upregulation of ephrin B1/EphB1 and ephrin B2/EphB2 in neuropathic pain of different etiology. The activation of the ephrin B/EphB system in the dorsal root ganglion and dorsal horn of the spinal cord may be essential in initiating and maintaining neuropathic pain. Accordingly, it can be proposed that the pharmacological inhibitors of EphB receptors may be potentially employed to manage the manifestations of pain. One of the primary mechanisms involved in ephrin B/EphB-mediated synaptic plasticity includes phosphorylation and activation of NMDA receptors, which may be secondary to activation of different kinases, including MAP kinases (MAPK), protein kinase C (PKC), and Src family kinases (SFK). The other molecular mechanisms may include activation of inflammatory cytokines in the spinal cord, caspase-3, calpain-1, phosphoinositide 3-kinase (PI3K), protein kinase A (PKA), and cAMP Response Element-Binding Protein (CREB). The present review discusses the role and molecular mechanisms involved in ephrin B/EphB-mediated neuropathic pain of different etiology.

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Myocardial ischemic injury is a primary cause of death among various cardiovascular disorders. The condition occurs due to interrupted blood supply and vital nutrients (necessary for normal cellular activities and viability) to the myocardium, eventually leading to damage. Restoration of blood supply to ischemic tissue is noted to cause even more lethal reperfusion injury. Various strategies, including some conditioning techniques like preconditioning & postconditioning have been developed to check detrimental effects of reperfusion injury. Many endogenous substances have been proposed to act as initiator, mediators and end effectors of these conditioning techniques. Substances like adenosine, bradykinin, acetylcholine, angiotensin, norepinephrine, opioids, etc., have been reported to mediate cardioprotective activity. Among these agents, adenosine has been widely studied and suggested to have the most pronounced cardioprotective effects. The current review article highlights the role of adenosine signaling in the cardioprotective mechanism of conditioning techniques. The article also provides an insight into various clinical studies that substantiate the applicability of adenosine as a cardioprotective agent in myocardial-reperfusion injury.

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The aim of the present study was to evaluate the role of Bacopa monnieri in acetic-acid-induced ulcerative colitis in mice. Acetic acid (3%v/v, in 0.9% saline) was infused intrarectally to induce ulceration in mice. Administration of acetic acid resulted in severe inflammation of the colon along with an increase in the myeloperoxidase (MPO) activity assessed on 7th day. Treatment with Bacopa monnieri extract (20 mg/kg and 40 mg/kg, p.o) and saponin-rich fraction (5 mg/kg and 10 mg/kg; p.o) for 7 days i.e. 2 days before and 5 days after acetic acid infusion, significantly attenuated the colonic inflammation in a dose-dependent manner. Furthermore, it also reduced the MPO levels and the disease activity score as compared to the control group. It may be concluded that Bacopa monnieri has the potential for ameliorating acetic-acid-induced colitis and its saponin-rich fraction may be responsible for this effect.

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Myocardial ischemic injury is a primary cause of death among various cardiovascular disorders. The condition occurs due to an interrupted supply of blood and vital nutrients (necessary for normal cellular activities and viability) to the myocardium, eventually leading to damage. Restoration of blood supply to ischemic tissue is noted to cause even more lethal reperfusion injury. Various strategies, including some conditioning techniques, like preconditioning and postconditioning, have been developed to check the detrimental effects of reperfusion injury. Many endogenous substances have been proposed to act as initiators, mediators, and end effectors of these conditioning techniques. Substances, like adenosine, bradykinin, acetylcholine, angiotensin, norepinephrine, opioids, etc., have been reported to mediate cardioprotective activity. Among these agents, adenosine has been widely studied and suggested to have the most pronounced cardioprotective effects. The current review article highlights the role of adenosine signaling in the cardioprotective mechanism of conditioning techniques. The article also provides an insight into various clinical studies that substantiate the applicability of adenosine as a cardioprotective agent in myocardial reperfusion injury.

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AIM: The study investigates the effect of Valsartan, an Angiotensin II type 1 receptor blocker (ARB), on the blunted neuroprotective response of ischemic post-conditioning (iPoCo) in rats subjected to High Fat Diet (HFD). BACKGROUND: The neuroprotective response of iPoCo is blunted in conditions of vascular endothelial dysfunction (ED) associated with hypercholesterolemia, diabetes, hypertension, etc. Objectives: The study was undertaken to investigate the effect of Valsartan, an ARB, on the blunted neuroprotective response of iPoCo in rats subjected to HFD. METHODS: Wistar rats were subjected to HFD for 56 days. The cerebral ischemic injury was induced by bilateral common carotid artery occlusion (BCCAO) for 12 min followed by reperfusion of 24 hrs. iPoCo was induced by three preceding cycles of ischemia and reperfusion lasting 1 min each given immediately after BCCAO at the onset of prolonged reperfusion. The extent of the injury was assessed in terms of memory impairment using the Morris Water Maze test (MWM), sensorimotor disturbance using the neurological severity score (NSS), and cerebral infarct size using triphenyl tetrazolium chloride staining. Series of biochemical estimations including brain thiobarbituric acid reactive species (TBARS); reduced glutathione (GSH); myeloperoxidase (MPO); tumor necrosis factor-α (TNF-α); Nrf-2 and serum cholesterol, serum nitrite levels were performed. RESULTS: BCCAO produced significant cerebral injury indicated by increased cerebral infarct size, memory impairment, increased NSS, and various biochemical alterations (increased cholesterol, TBARS, MPO, TNF-α, Nrf-2, and decreased nitrite and GSH levels). Significant neutrophil infiltration was also observed. iPoCo attenuated BCCAO-induced injury with respect to the above parameters in normal rats. The protective response of iPoCo was lost in HFD-treated rats. Treatment of Valsartan attenuated cerebral injury, potentiated the neuroprotective response of iPoCo in normal rats, and also restored the blunted neuroprotective effect of iPoCo in HFD-treated rats along with enhanced Nrf-2 levels. CONCLUSION: Valsartan exerted a neuroprotective effect by virtue of its multiple actions with a crucial role of Nrf2 activation.

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Depression is the most common mental health disorder worldwide; however, the exact cellular and molecular mechanisms of this major depressive disorder are unclear so far. Experimental studies have demonstrated that depression is associated with significant cognitive impairment, dendrite spine loss, and reduction in connectivity among neurons that contribute to symptoms associated with mood disorders. Rho/Rho-associated coiled-coil containing protein kinase (ROCK) receptors are exclusively expressed in the brain and Rho/ROCK signaling has gained considerable attention as it plays a crucial role in the development of neuronal architecture and structural plasticity. Chronic stress-induced activation of the Rho/ROCK signaling pathway promotes neuronal apoptosis and loss of neural processes and synapses. Interestingly, accumulated evidence has identified Rho/ROCK signaling pathways as a putative target for treating neurological disorders. Furthermore, inhibition of the Rho/ROCK signaling pathway has proven to be effective in different models of depression, which signify the potential benefits of clinical Rho/ROCK inhibition. The ROCK inhibitors extensively modulate antidepressant-related pathways which significantly control the synthesis of proteins, and neuron survival and ultimately led to the enhancement of synaptogenesis, connectivity, and improvement in behavior. Therefore, the present review refines the prevailing contribution of this signaling pathway in depression and highlighted preclinical shreds of evidence for employing ROCK inhibitors as disease-modifying targets along with possible underlying mechanisms in stress-associated depression.

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Neuropathic Pain is caused by damage to a nerve or disease of the somatosensory nervous system. Apart from the blood pressure regulating actions of angiotensin ligands, studies have shown that it also modulates neuropathic pain. In the animal models including surgical, chemotherapeutic, and retroviral-induced neuropathic pain, an increase in the levels of angiotensin II has been identified and it has been proposed that an increase in angiotensin II may participate in the induction of neuropathic pain. The pain-inducing actions of the angiotensin system are primarily due to the activation of AT1 and AT2 receptors, which trigger the diverse molecular mechanisms including the induction of neuroinflammation to initiate and maintain the state of neuropathic pain. On the other hand, the pain attenuating action of the angiotensin system has been attributed to decreasing in the levels of Ang(1-7), and Ang IV and an increase in the levels of bradykinin. Ang(1-7) may attenuate neuropathic pain via activation of the spinal Mas receptor. However, the detailed molecular mechanism involved in Ang(1-7) and Ang IV-mediated pain attenuating actions needs to be explored. The present review discusses the dual role of angiotensin ligands in neuropathic pain along with the possible mechanisms involved in inducing or attenuating the state of neuropathic pain.

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Arsenic exposure to the population leads to serious health problems like neurotoxicity, nephrotoxicity, and cardiovascular abnormality. In the present study, the work has been commenced to discover the prospect of rolipram a phosphodiestrase-4 (PDE-4) inhibitor against sodium arsenite (SA)-induced vascular endothelial dysfunction (EnDF) leading to dementia in rats. Wistar rats were treated with SA (5 mg/kg body weight/day orally) for 44 days for induction of vascular EnDF and dementia. Learning and memory were evaluated using Morris water maze (MWM) test. Vascular EnDF was evaluated using aortic ring preparation. Various biochemical parameters were also evaluated like brain oxidative stress (viz. reduced glutathione and thiobarbituric acid reactive substances level), serum nitrite/nitrate activity, acetylcholinesterase activity, and inflammatory markers (viz. neutrophil infiltration in brain and myeloperoxidase). SA-treated rats showed poor performance in water maze trials indicating attenuated memory and ability to learn with significant rise (p < 0.05) in brain acetylcholinesterase activity, brain oxidative stress, neutrophil count, and significant decrease (p < 0.05) in serum nitrite/nitrate levels and vascular endothelial functions. Rolipram (PDE-4 inhibitor) treatment (0.03 mg/kg and 0.06 mg/kg body weight, intraperitoneally daily for 14 days) significantly improved memory and learning abilities, and restored various biochemical parameters and EnDF. It is concluded that PDE-4 modulator may be considered the prospective target for the treatment of SA-induced vascular EnDF and related dementia.

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OBJECTIVES: The study has been commenced to discover the potential of Phlorizin (dual SGLT inhibitor) in streptozotocin induced dementia of Alzheimer's disease (AD) type. MATERIAL AND METHODS: Injection of Streptozotocin (STZ) was given via i.c.v. route (3 mg/kg) to induce dementia of Alzheimer's type. In these animals learning and memory was evaluated using Morris water maze (MWM) test. Glutathione (GSH) and thiobarbituric acid reactive species (TBARS) level was quantified to evaluate the oxidative stress; cholinergic activity of brain was estimated in term of acetylcholinesterase (AChE) activity; and the levels of myeloperoxidase (MPO) were measured as inflammation marker. RESULTS: The mice model had decreased performance in MWM, representing impairment of cognitive functions. Biochemical evaluation showed rise in TBARS level, MPO and AChE activity, and fall in GSH level. The histopathological study revealed severe infiltration of neutrophils. In the study, Phlorizin/Donepezil (serving as positive control) treatment mitigate streptozotocin induced cognitive decline, histopathological changes and biochemical alterations. CONCLUSIONS: The results suggest that Phlorizin decreased cognitive function via its anticholinesterase, antioxidative, antiinflammatory effects and probably through SGLT inhibitory action. It can be conferred that SGLTs can be an encouraging target for the treatment of dementia of AD.

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Ischemia refers to a reduced supply of oxygen and nutrient to the vital organ of the body. Reperfusion to the ischemic organ is the only way to salvage injury due to ischemia. Paradoxically, reperfusion itself induces the injury, which is more severe than the previous injury referred to as ischemia-reperfusion injury. Ischemia-reperfusion injury is the major cause of mortality in the case of ischemic diseases. The major hurdle for a clinician to treat ischemia is the reperfusion injury, which is encountered in different surgical as well as non-surgical situations. Several therapies, such as anti-platelets, anti-thrombolytic agents have been developed to contain ischemia-reperfusion injury, but with limited success. Over some time, some conditioning techniques such as preconditioning and postconditioning have been used by clinicians to overcome ischemia-reperfusion injury. The present review focuses on the clinical applications of different conditioning techniques in diverse pathological conditions of ischemia-reperfusion injury.

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In the past 10 years, mortality from acute myocardial infarction has not decreased despite the widespread introduction of percutaneous coronary intervention. The reason for this situation is the absence in clinical practice of drugs capable of preventing reperfusion injury of the heart with high efficiency. In this regard, noteworthy natriuretic peptides (NPs) which have the infarct-limiting effect, prevent reperfusion cardiac injury, prevent adverse post-infarction remodeling of the heart. Atrial natriuretic peptide does not have the infarct-reducing effect in rats with alloxan-induced diabetes mellitus. NPs have the anti-apoptotic and anti-inflammatory effects. There is indirect evidence that NPs inhibit pyroptosis and autophagy. Published data indicate that NPs inhibit reactive oxygen species production in cardiomyocytes, aorta, heart, kidney and the endothelial cells. NPs can suppress aldosterone, angiotensin II, endothelin-1 synthesize and secretion. NPs inhibit the effects aldosterone, angiotensin II on the post-receptor level through intracellular signaling events. NPs activate guanylyl cyclase, protein kinase G and protein kinase A, and reduce phosphodiesterase 3 activity. NO-synthase and soluble guanylyl cyclase are involved in the cardioprotective effect of NPs. The cardioprotective effect of natriuretic peptides is mediated via activation of kinases (AMPK, PKC, PI3 K, ERK1/2, p70s6 k, Akt) and inhibition of glycogen synthase kinase 3ß. The cardioprotective effect of NPs is mediated via sarcolemmal KATP channel and mitochondrial KATP channel opening. The cardioprotective effect of brain natriuretic peptide is mediated via MPT pore closing. The anti-fibrotic effect of NPs may be mediated through inhibition TGF-ß1 expression. Natriuretic peptides can inhibit NF-κB activity and activate GATA. Hemeoxygenase-1 and peroxisome proliferator-activated receptor γ may be involved in the infarct-reducing effect of NPs. NPs exhibit the infarct-limiting effect in patients with acute myocardial infarction. NPs prevent post-infarction remodeling of the heart. To finally resolve the question of the feasibility of using NPs in AMI, a multicenter, randomized, blind, placebo-controlled study is needed to assess the effect of NPs on the mortality of patients after AMI.

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AIM: The present study was designed to investigate the role of nitric oxide (NO) in the non-development of stress adaptation in high-intensity foot-shock stress (HIFS) subjected mice. METHODS: Mice were subjected to low-intensity shocks (LIFS i.e. 0.5 mA) or HIFS (1.5 mA) for 5 days. Stress-induced behavioral changes were assessed by actophotometer, hole board, open field and social interaction tests. Biochemically, the serum corticosterone levels were measured as a marker of stress. L-arginine (100 mg/kg and 300 mg/kg), as NO donor, and L-NAME (10 mg/kg and 30 mg/kg), as nitric oxide synthase (NOS) inhibitor, were employed as pharmacological agents. RESULTS: A single exposure of LIFS and HIFS produced behavioral and biochemical alterations. However, there was the restoration of behavioral and biochemical alterations on 5th day in response to repeated LIFS exposure suggesting the development of stress adaptation. However, no stress adaptation was observed in HIFS subjected mice. Administration of L-arginine (300 mg/kg) abolished the stress adaptive response in LIFS-subjected mice, while L-NAME (30 mg/kg) induced the development of stress adaptation in HIFS subjected mice. CONCLUSION: It is concluded that an increase in the NO release may possibly impede the process of stress adaptation in HIFS-subjected mice.

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AIM: The study has been commenced to discover the potential of sodium dependent glucose co-transporters (SGLT) in neuroprotective mechanism of ischemic postconditioning (iPoCo) in diabetic and non-diabetic mice. METHODS: Cerebral ischemic injury in mice was induced by bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 hr. For iPoCo, three episodes of carotid artery reperfusion and occlusion of 10 sec each were instituted immediately after BCAO, followed by 24 hr reperfusion. Learning and memory were evaluated using the Morris water maze test. Motor coordination was assessed using rotarod test, inclined beam walking test, neurological severity score (NSS), and lateral push response. Glutathione and Thiobarbituric acid reactive species level was quantified to evaluate the oxidative stress; the cholinergic activity of the brain was estimated in terms of acetylcholinestrase activity, and the levels of myeloperoxidase were measured as inflammation marker. Cerebral infarct size was evaluated using triphenyltetrazolium chloride staining. Fasting blood glucose levels of animals were taken before and 6 hr after the surgical procedure. RESULTS: BCAO resulted in impairment of memory and motor coordination and biochemical alterations along with a marked rise in cerebral infarct size and NSS. iPoCo diminished the deadly effect of BCAO in non-diabetic mice; however, it failed to abolish the deleterious effects of ischemia- reperfusion injury in diabetic mice. Pretreatment of Phlorizin (SGLT-inhibitor) potentiated the neuroprotective effects of iPoCo in non-diabetics and restored the protective effect of iPoCo in diabetic mice. CONCLUSION: It may be concluded that the neuroprotective effect of iPoCo is abolished in diabetic mice, and SGLT plays an important role in neuroprotection.

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Silent information regulator-1 (SIRT-1), is a member of the class III group of histone deacetylases and is collectively called sirtuins. There have been preclinical and clinical studies indicating the downregulation and decreased activity of sirtuin 1 in various inflammatory bowel disease models. Furthermore, the downregulation of sirtuin 1 is responsible for the sustained production of proinflammatory cytokines and the generation of oxidative stress in colitis. Hyperacetylation of NF-κB and HSF-1 (heat shock factor-1) in the absence of sirtuin1 is responsible for the induction of colitis. Accordingly, exogenous administration of sirtuin1 activators has been shown to attenuate the colitis in various inflammatory bowel disease models. On the other hand, the knockdown of sirtuin 1 gene or pharmacologic inhibition of sirtuin 1 has also been shown to be protective in the colitis. The deletion of the sirtuin1 gene may be helpful in the improvement of the disease condition of colitis through the maintenance of gastrointestinal immune homeostasis. The current review highlights the dual role of sirtuin 1 in the different experimental models of IBD along with possible mechanisms.

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Objectives The present study was designed to investigate the effectiveness of trihexyphenidyl, a central anticholinergic drug, in preventing the post-traumatic stress disorder (PTSD) symptoms in a mouse model. Methods Mice were subjected to underwater trauma stress for 30 s on day 1 followed by three situational reminders (3rd, 7th and 14th day). Thereafter, the behavioral alterations including freezing behavior were noted on 21st day. The serum corticosterone levels were measured as a biochemical marker of trauma. Elevated plus maze test was done on day 1 and day 2 to assess the memory formation following exposure to trauma. Results Trauma and situational reminders were associated with a significant development of behavioral changes and freezing behavior on the 21st day. Moreover, there was also a significant decrease in the serum corticosterone levels. A single administration of trihexyphenidyl (2 and 5 mg/kg) significantly restored trauma associated-behavioral changes and serum corticosterone levels. Moreover, it significantly increased the transfer latency time on day 2 following stress exposure in comparison to normal mice suggesting the inhibition of memory formation during trauma exposure. Trihexyphenidyl also led to significant reduction in freezing behavior in response to situational reminders again suggesting the inhibition of formation of aversive fear memory. Conclusion The blockade of central muscarinic receptors may block the formation of aversive memory during the traumatic event, which may be manifested in form of decreased contextual fear response during situational reminders. Central anticholinergic agents may be potentially useful as prophylactic agents in preventing the development of PTSD symptoms.

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Remote ischemic preconditioning (RIPC) is an intrinsic protective phenomenon in which 3 to 4 interspersed cycles of non-fatal regional ischemia followed by reperfusion to the remote tissues protect the vital organs including brain, heart and kidney against sustained ischemia-reperfusion-induced injury. There is growing preclinical evidence supporting the usefulness of RIPC in eliciting neuroprotection against focal and global cerebral ischemia-reperfusion injury. Scientists have explored the involvement of HIF-1α, oxidative stress, apoptotic pathway, Lcn-2, platelets-derived microparticles, splenic response, adenosine A1 receptors, adenosine monophosphate activated protein kinase and neurogenic pathway in mediating RIPC-induced neuroprotection. The present review discusses the early and late phases of neuroprotection induced by RIPC against cerebral ischemic injury in animals along with the various possible mechanisms.

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OBJECTIVES: The role of N-acetylcysteine (NAC) as an anti-oxidant in attenuating bleomycin-induced pulmonary fibrosis has been reported. However, its effect on parenchymal remodeling via regulating the protease-antiprotease balance is not fully defined. Therefore, the present study was designed to explore the possible role of matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and transforming growth factor-ß1 (TGF-ß1) pathway and their modulation by NAC in attenuating bleomycin-induced pulmonary fibrosis in rats. MATERIALS AND METHODS: Bleomycin sulphate (7 units/kg) was instilled inside the trachea to induce pulmonary fibrosis. The time course of TGF-ß1, MMP-9, TIMP-1,3 mRNA and protein expression, TGF-ß1 and hydroxyproline levels were evaluated on days 7, 14, and 28. NAC (0.3 mmol/kg and 3 mmol/kg) was administered in bleomycin-instilled animals. RESULTS: NAC treatment significantly attenuated bleomycin-induced histopathological changes by decreasing interstitial inflammation and reducing the deposition of extracellular matrix proteins such as collagen. Moreover, it increased the mRNA and protein expression of MMP-9 and decreased the expression of TIMP-1,3 in alveolar epithelial cells (AECs), interstitial macrophages and inflammatory cells. Indeed, there was decrease in the MMP-9/TIMP ratio in bleomycin-instilled rats, which increased with NAC treatment. Moreover, NAC attenuated bleomycin-induced increased expression of TGF-ß1 and total lung collagen levels. CONCLUSION: NAC attenuates bleomycin-induced pulmonary fibrosis by normalizing the protease-antiprotease balance and favoring the degradation of collegen to reduce fibrosis.