Clinical Applicability of Conditioning Techniques in Ischemia-Reperfusion Injury: A Review of the Literature.

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.

The Role of Natriuretic Peptides in the Regulation of Cardiac Tolerance to Ischemia/Reperfusion and Postinfarction Heart Remodeling.

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.

Impact of cold adaptation on cardiac tolerance to ischemia/reperfusion and glucocorticoid, thyroid hormone levels.

We have established that the continuous cold exposure (CCE, 4°C, 4 weeks) causes cold adaptation, increases systolic blood pressure, exerts infarct-limiting effect during coronary artery occlusion (45 min) and reperfusion (2 h). The CCE increases adrenal weight, heart weight and triiodothyronine (T3) level but does not change thymus, spleen weight, serum cortisol, corticosterone and thyroxin (T4) levels. The long-term (4°C, 8 h/day, 4 weeks) intermittent cold exposure (LICE) induces adaptation to the cold and increases T4 level. The brief (4°C, 1.5 h/day, 4 weeks) intermittent cold exposure (BICE) also evokes adaptation to the cold but had no effect on the blood pressure, the cardiac tolerance to ischemia/reperfusion, and does not change thymus, spleen weight, serum cortisol, corticosterone, T3 and T4 levels.

Physiological and Pathological Role of TRPV1, TRPV2 and TRPV4 Channels in Heart.

Transient receptor potential vanilloid channel 2 (TRPV2) is required for normal cardiac contractility. The stimulation of TRPV1 in isolated cardiomyocytes can aggravate the effect of hypoxia/ reoxygenation (H/R) on H9C2 cells. The knockout of the TRPV1 gene promotes increased tolerance of the isolated perfused heart to the impact of ischemia/reperfusion (I/R). However, activation of TRPV1 increases the resistance of the heart to I/R due to calcitonin gene-related peptide (CGRP) release from afferent nerve endings. It has been established that TRPV1 and TRPV2 are involved in the pathogenesis of myocardial infarction and, in all likelihood, ensure the cardiac tolerance to the ischemia/reperfusion. It has also been documented that the activation of TRPV4 negatively affects the stability of cardiomyocytes to the H/R. The blockade of TRPV4 can be considered as a new approach to the prevention of I/R injury of the heart. Studies also indicate that TRPV1 is involved in the pathogenesis of cardiac hypertrophy and that TRPV2 channels participate in the pathogenesis of dilated cardiomyopathy. Excessive expression of TRPV2 leads to chronic Ca2+- overload of cardiomyocytes, which may contribute to the development of cardiomyopathy.

Reactive Oxygen Species as Intracellular Signaling Molecules in the Cardiovascular System.

BACKGROUND: Redox signaling plays an important role in the lives of cells. This signaling not only becomes apparent in pathologies but is also thought to be involved in maintaining physiological homeostasis. Reactive Oxygen Species (ROS) can activate protein kinases: CaMKII, PKG, PKA, ERK, PI3K, Akt, PKC, PDK, JNK, p38. It is unclear whether it is a direct interaction of ROS with these kinases or whether their activation is a consequence of inhibition of phosphatases. ROS have a biphasic effect on the transport of Ca2+ in the cell: on one hand, they activate the sarcoplasmic reticulum Ca2+-ATPase, which can reduce the level of Ca2+ in the cell, and on the other hand, they can inactivate Ca2+-ATPase of the plasma membrane and open the cation channels TRPM2, which promote Ca2+-loading and subsequent apoptosis. ROS inhibit the enzyme PHD2, which leads to the stabilization of HIF-α and the formation of the active transcription factor HIF. CONCLUSION: Activation of STAT3 and STAT5, induced by cytokines or growth factors, may include activation of NADPH oxidase and enhancement of ROS production. Normal physiological production of ROS under the action of cytokines activates the JAK/STAT while excessive ROS production leads to their inhibition. ROS cause the activation of the transcription factor NF-κB. Physiological levels of ROS control cell proliferation and angiogenesis. ROS signaling is also involved in beneficial adaptations to survive ischemia and hypoxia, while further increases in ROS can trigger programmed cell death by the mechanism of apoptosis or autophagy. ROS formation in the myocardium can be reduced by moderate exercise.

Design, synthesis, and biological evaluation of 2-substituted-2,3,4,9-tetrahydrospiro-ß-carboline-3-carboxylic acid derivatives as first-in-class mast cell stabilizers.

Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic rhinitis, and conjunctivitis as well as anaphylactic shock; hence, there is an unmet need for developing new mast cells stabilizers. The reported mast cell stabilizers have a heterocyclic moiety and an acidic group. Furthermore, the role of tryptophan in suppression of mast cell activation is established. Hence, we prepared constrained analogs of tryptophan, which are derivatives of 2,3,4,9-tetrahydrospiro-ß-carboline-3-carboxylic acid, and evaluated them for ex vivo inhibition of compound 48/80-induced mast degranulation activity. By comparing IC50 (µM) values with that of the standard drug sodium cromoglycate (IC50 = 0.489 ± 0.003 µM), compounds with bulky groups like heptyl (compound 9; IC50 = 0.389 ± 0.015 µM) and octyl (compound 10; IC50 = 0.354 ± 0.023 µM) were found to be of similar potency as sodium cromoglycate. Furthermore, the polar group-containing compounds like the chloropropyl (compound 16; IC50 = 0.382 ± 0.083 µM) and benzoyl derivative (compound 14; IC50 = 00.469 ± 0.032 µM) were also found to be of similar potency as sodium cromoglycate. This is a seminal study of spiro-ß-carboline mast cell stabilization having a wider scope in mast cell research; yet, the mechanism of action remains elusive.

Potential of carnosine, a histamine precursor in rat model of bilateral common carotid artery occlusion-induced vascular dementia.

The present study investigates the potential of Carnosine, a histamine precursor in rat model of bilateral common carotid artery occlusion (BCCAo)-induced vascular dementia (VaD). Wistar rats were subjected to BCCAo procedure under anaesthesia to induce VaD. The rats were subjected to Morris water maze (MWM) test (6th day onwards post-surgery). MWM test was employed to assess learning and memory of the animals whereby escape latency time, time spent in target quadrant and Path length (distance travelled) taken as important parameters. Serum nitrite level; Brain thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) levels; Brain acetylcholinesterase (AChE) activity; brain Myeloperoxidase activity (MPO) and neutrophil count were estimated as per standard procedures. BCCAo in rats produced a significant vascular endothelial dysfunction, as reflected by decrease in serum nitrite levels. Further, these animals showed poor performance on MWM, depicting impairment of learning and memory. There was a significant rise in brain oxidative stress level as indicated by increase in TBARS and decrease in GSH levels. An increase in brain AChE activity was also observed. Moreover, these rats also exhibited an increase in MPO activity and neutrophil infiltration in brain (as marker of inflammation). Treatment of Carnosine (200 and 400 mg/kg, i.p.)/Donepezil (0.3 mg/kg, i.p.) ameliorated BCCAo-induced memory deficits; endothelial dysfunction; biochemical and histopathological changes. It is concluded that Carnosine has shown efficacy in rat model of BCCAo-induced VaD and can be considered as an important therapeutic agent for the treatment of VaD.

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.

Evidence for the role of histaminergic pathways in neuroprotective mechanism of ischemic postconditioning in mice.

The present study has been designed to investigate the possible role of histaminergic pathway in neuroprotective mechanism of ischemic postconditioning (iPoCo). Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce I/R-induced cerebral injury in National Institutes of Health mice mice. iPoCo involving three episodes of carotid artery occlusion and reperfusion of 10 sec each was instituted immediately after BCAO just before prolonged reperfusion. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using Morris water maze test. Rotarod test, inclined beam-walking test, and neurological severity score (NSS) were performed to assess motor incoordination and sensorimotor abilities. Brain acetylcholine esterase (AChE) activity, brain myeloperoxidase (MPO) activity, brain thiobarbituric acid-reactive species (TBARS), and glutathione level (GSH) were also estimated. BCAO produced a significant rise in cerebral infarct size and NSS along with impairment of memory and motor coordination and biochemical alteration (↑AChE, ↑MPO ↓GSH, and ↑TBARS). iPoCo attenuated the deleterious effect of BCAO on infarct size, memory, NSS, motor coordination, and biochemical markers. Pretreatment of carnosine (a histamine [HA] precursor) potentiated the neuroprotective effects of iPoCo, whereas pretreatment of ketotifen (HA H1 receptor blocker and mast cell stabilizer) abolished the protective effects of iPoCo as well as that of carnosine on iPoCo. It may be concluded that neuroprotective effect of iPoCo probably involves activation of histaminergic pathways.

Silymarin and Its Role in Chronic Diseases.

Silymarin is the active constituent of Silybum marianum (milk thistle) which is a C-25 containing flavonolignan. Milk thistle has a lot of traditional values, being used as a vegetable, as salad, as bitter tonic, and as galactogogue in nursing mothers and in various ailments such as liver complications, depression, dyspepsia, spleenic congestions, varicose veins, diabetes, amenorrhea, uterine hemorrhage, and menstrual problems. In this present chapter, a comprehensive attempt has been made to discuss the potential of silymarin in chronic disorders. An insight into modulation of cellular signaling by silymarin and its implication in various disorders such as liver disorders, inflammatory disorders, cancer, neurological disorders, skin diseases, and hypercholesterolemia is being provided.

Investigating the role of nisoldipine in foot-shock-induced post-traumatic stress disorder in mice.

This study was designed to investigate the effectiveness of nisoldipine, an L-type voltage-sensitive calcium channel blocker, to ameliorate anxiety and fear response in a mouse model of post-traumatic stress disorder (PTSD). Acute trauma was induced in Swiss albino mice in a 2-day electric foot-shock paradigm consisting of 15 intermittent foot-shocks of 0.8 mA intensity, 10-s duration and 10-s intershock interval, during 5 min, followed by 3 weekly situational reminders, that is, once per week in the same context on three successive weeks. PTSD-induced behavioral changes were assessed using actophotometer, open-field, social interaction test, and freezing behavior. Biochemically, the serum corticosterone levels were estimated. Electric foot-shock and situational reminders produced behavioral alterations and decreased corticosterone levels, assessed on the 21st day following the traumatic event. Administration of sertraline (Ser 15 mg/kg), a selective serotonin reuptake inhibitor (SSRI) and nisoldipine (20 and 40 mg/kg), significantly attenuated the foot-shock-trauma-induced behavioral changes along with normalization of the corticosterone levels. It may be concluded that nisoldipine produces beneficial effects in re-establishing behavioral alterations, which may be due to normalization of reduced corticosterone levels in PTSD in mice.

Efficacy of Cilostazol a selective phosphodiesterase-3 inhibitor in rat model of Streptozotocin diabetes induced vascular dementia.

The present study has been designed to investigate the potential of Cilostazol a phosphodiesterase-3 (PDE-3) inhibitor in diabetes-induced vascular dementia (Vad) employing Wistar rats. A single dose of Streptozotocin (STZ) was used for the induction of diabetes and subsequent Vad in rats. Memory and learning abilities of rats were evaluated with Morris water maze (MWM) test. Serum glucose, body weight, vascular endothelial function, serum nitrite/nitrate levels, brain oxidative stress levels (viz. brain thiobarbituric acid reactive species and reduced glutathione levels), inflammatory markers (viz. brain myeloperoxidase activity and neutrophil infiltration in the brain hippocampal area) and brain acetylcholinesterase activity were also tested. Donepezil was used as positive control. Streptozotocin treated animals showed poor performance on MWM indicating impairment of learning and memory abilities with a significant reduction in body weight, vascular endothelial function, serum nitrite/nitrate levels, along with an increase in serum glucose, brain oxidative stress levels, inflammatory changes and brain acetylcholinesterase activity. Treatment with selective PDE-3 inhibitor, Cilostazol significantly attenuated, diabetes-induced impairment of learning and memory; endothelial dysfunction, and changes in various biochemical parameters. It is concluded that selective PDE-3 inhibitor, Cilostazol may be considered as the potential pharmacological agent for the management of diabetes-induced vascular dementia.

Pharmacologic investigations on the role of Sirt-1 in neuroprotective mechanism of postconditioning in mice.

BACKGROUND: Cerebral ischemia-reperfusion (I-R) injury is one of the primary causes of ischemic stroke. Ischemic postconditioning (iPoCo) is evolving as an important adaptive technique to contain I-R injury. Some recent studies have shown neuroprotective effects of iPoCo. However, the neuroprotective mechanism of iPoCo is not clear. So, the present study has been undertaken to investigate the possible role of Sirtinol, a selective class III histone deacetylase (HDAC) inhibitor in the neuroprotective mechanism of iPoCo in mice. MATERIAL AND METHODS: Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was used to produce I-R-induced cerebral injury in Swiss albino mice. iPoCo involving three episodes of 10-s carotid artery occlusion and reperfusion instituted immediately after BCAO just before prolonged reperfusion of 24 h. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using a Morris water maze test. Rotarod test, inclined beam-walking test, and neurologic severity score (NSS) were used to assess motor incoordination. Acetylcholine esterase levels, brain thiobarbituric acid reactive species (TBARS), and glutathione level were also estimated. RESULTS: BCAO for 12 min followed by reperfusion for 24 h produced a significant rise in cerebral infarct size and NSS along with impairment of memory and motor coordination and biochemical alteration (↑acetylcholine esterase, ↓glutathione, and ↑TBARS). iPoCo, involving three episodes of 10-s carotid artery occlusion with intermittent reperfusion of 10 s applied just after ischemic insult of 12 min produced a significant decrease in cerebral infarct size and NSS along with the reversal of I-R-induced impairment of memory and motor coordination. iPoCo-induced neuroprotective effects were significantly abolished by pretreatment with selective SIRT 1 (class III HDAC) blocker Sirtinol (10 mg/kg intraperitoneal). CONCLUSIONS: It may be concluded that the neuroprotective effect of iPoCo probably involves activation of SIRT 1 (class III HDAC) enzyme.

Possible role of pannexin 1/P2x7 purinoceptor in neuroprotective mechanism of ischemic postconditioning in mice.

BACKGROUND: Previous studies have suggested a significant role of pannexin 1 (Panx1)/P2X7 receptor complex in cardioprotective mechanism of ischemic preconditioning and postconditioning (IPC). The present study has been undertaken to investigate whether Panx1/P2X7 purinoceptors are also involved in the neuroprotective mechanism of IPC in mice. MATERIALS AND METHODS: Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was used to produce ischemia-reperfusion-induced cerebral injury in Swiss albino mice. For IPC immediately after BCAO of 12 min, three cycles of 10-s ischemia and reperfusion each were given and then prolonged reperfusion of 24 h was used. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using a Morris water maze test. Rotarod test, inclined beam walking test, and neurologic severity score (NSS) were used to assess motor dysfunction. Acetylcholine esterase levels, brain thiobarbituric acid reactive species, and glutathione level were also estimated. RESULTS: BCAO followed by reperfusion produced a significant increase in cerebral infarct size, NSS along with impairment of memory and motor dysfunction. It also increased brain acetylcholine esterase, thiobarbituric acid reactive species levels, and decreased the glutathione level. IPC produced a significant decrease in the cerebral infarct size and NSS along with reversal of ischemia-reperfusion-induced impairment of memory, motor dysfunction, and altered biochemical levels in the brain. IPC-induced neuroprotective effects were significantly abolished by pretreatment of mefloquine (15.0 mg/kg orally; 30.0 mg/kg orally), blocker of Panx1/P2X7 purinoceptor. CONCLUSIONS: Therefore, activation of Panx1/P2X7 purinoceptors appears to play a significant role in the neuroprotective mechanism of IPC.

Ameliorative potential of Ocimum sanctum in chronic constriction injury-induced neuropathic pain in rats.

The present study was designed to investigate the ameliorative potential of Ocimum sanctum and its saponin rich fraction in chronic constriction injury-induced neuropathic pain in rats. The chronic constriction injury was induced by placing four loose ligatures around the sciatic nerve, proximal to its trifurcation. The mechanical hyperalgesia, cold allodynia, paw heat hyperalgesia and cold tail hyperalgesia were assessed by performing the pinprick, acetone, hot plate and cold tail immersion tests, respectively. Biochemically, the tissue thio-barbituric acid reactive species, super-oxide anion content (markers of oxidative stress) and total calcium levels were measured. Chronic constriction injury was associated with the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia along with an increase in oxidative stress and calcium levels. However, administration of Ocimum sanctum (100 and 200 mg/kg p.o.) and its saponin rich fraction (100 and 200 mg/kg p.o.) for 14 days significantly attenuated chronic constriction injury-induced neuropathic pain as well as decrease the oxidative stress and calcium levels. It may be concluded that saponin rich fraction of Ocimum sanctum has ameliorative potential in attenuating painful neuropathic state, which may be attributed to a decrease in oxidative stress and calcium levels.

Pharmacology of Src family kinases and therapeutic implications of their modulators.

Src family kinases (SFKs), the largest family of nonreceptor tyrosine kinases, include 10 members. Src was the first gene product discovered to have intrinsic protein tyrosine kinase activity. Src is widely expressed in many cell types and can have different locations within a cell; the subcellular location of Src can affect its function. Src can associate with cellular membranes, such as the plasma membrane, the perinuclear membrane, and the endosomal membrane. SFKs actions on mammalian cells are pleiotropic and include effect on cell morphology, adhesion, migration, invasion, proliferation, differentiation, and survival. SFKs at one end have been documented to play some important physiological functions; on the other end, they have been described in the pathophysiology of some disorders. In this review article, an exhaustive attempt has been made to unearth pharmacology of SFKs and therapeutic implications of SFKs modulators.

Animal models of dementia and cognitive dysfunction.

Recent advances in the understanding of the pathophysiological mechanisms underlying Alzheimer's disease and other cognitive deficits have pointed to novel strategies for drug development. Animal models have contributed noticeably to these advances and are an indispensible part in the evaluation of therapeutics. This review is an exhaustive study of animal models of dementia and cognitive dysfunction. A thorough and critical evaluation of current rodent models of dementia, and discussion about their role in drug discovery and development have been carried out. Since dementia has multiple pathophysiological mechanisms, we have tried to provide a detailed description of various types of animal models which would depict different pathophysiological stages and causes of dementia. This review aims to better understand the prognosis, biochemical, and behavioral alterations that occur during dementia and hence facilitate drug discovery and development.

Ameliorative Effect of a Selective Endothelin ETA Receptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia.

The present study was designed to investigate the efficacy of selective ETA receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5(th) to 8(th) week of L-methionine treatment). On 52(nd) day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective ETA receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.

Silymarin ameliorates memory deficits and neuropathological changes in mouse model of high-fat-diet-induced experimental dementia.

A huge body evidences suggest that obesity is the single great risk factor for the development of dementia. Recently, silymarin, a flavonoid, clinically in use as a hepatoprotectant, has been reported to prevent amyloid beta-induced memory impairment by reducing oxidative stress and inflammation in mice brain. However, its potential in high-fat-diet (HFD)-induced dementia has not yet been investigated. Therefore, the present study is designed to explore the role of silymarin in HFD-induced experimental dementia in mice. Morris water maze test was employed to assess learning and memory. Various biochemical estimations including brain acetylcholinerstarse activity (AchE), thiobarbituric acid-reactive species (TBARS) level, reduced glutathione level (GSH), nirate/nitrite, and myeloperoxidase (MPO) activity were measured. Serum cholesterol level was also determined. HFD significantly impaired the cognitive abilities, along with increasing brain AchE, TBARS, MPO, nitrate/nitrite, and serum cholesterol levels. Marked reduction of brain GSH levels was observed. On the contrary, silymarin significantly reversed HFD-induced cognitive deficits and the biochemical changes. The present study indicates strong potential of silymarin in HFD-induced experimental dementia.

Pharmacological investigations on possible role of Src kinases in neuroprotective mechanism of ischemic postconditioning in mice.

The present study has been undertaken to investigate the possible role of Src Kinases in a neuroprotective mechanism of ischemic postconditioning in mice. Bilateral carotid artery occlusion for 12 min followed by reperfusion for 24 h produced a significant increase in cerebral infarct size and neurological severity score along with impairment of memory and motor coordination. Ischemic postconditioning involving three episodes of 10 s carotid artery occlusion with intermittent reperfusion of 10 s proceeding ischemic insult of 12 min, produced a significant decrease in cerebral infarct size and neurological severity score along with reversal of ischemia-reperfusion induced impairment of memory and motor coordination. Ischemic postconditioning induced neuroprotective effects were significantly attenuated by pre-treatment of selective Src Kinase inhibitors SU-6656 (4 mg/kg i.p.) and PP1 (0.2 mg/kg i.p.). It may be concluded that the neuroprotective effect of ischemic postconditioning probably involves activation of Src Kinase pathway.