Flavone-based novel antidiabetic and antidyslipidemic agents.

The hybrid congeners 62-90 of 6- and 7-hydroxyflavones with aminopropanol have been synthesized and evaluated for their antidiabetic activity in sucrose-challenged low-dosed streptozotocin (STZ)-induced diabetic rats and db/db mice. The optical enantiomers 70a, 70b, 90a, and 90b of two congeners 70 and 90 exhibiting consistent antidiabetic and antidyslipidemic activities were also prepared, and their antidiabetic activity results indicate its association mainly with S isomers. These compounds also lower cholesterol and TG profiles while improving high-density lipoprotein cholesterol to CHOL ratio in db/db mice. The bioavailability of compound 70 and its isomer varies between 27 and 29% whereas that of the more polar compound 90a is poor as determined in rat by oral and intraperitoneal administrations.

Neuroprotection by rosiglitazone in transient focal cerebral ischemia might not be mediated by glutamate transporter-1.

Glutamate transport represents a key mechanism for maintaining low level of glutamate in the extracellular milieu to restrict the excitotoxic action of glutamate released during ischemia/reperfusion (I/R) injury. Recently, it has been reported that glutamate transporter-1 (GLT-1) is a novel target for peroxisome proliferator-activated receptor-γ (PPARγ) agonist, which shows neuroprotection following oxygen glucose deprivation (OGD) in neuronal-astrocytic cocultures. Hence, the present study was undertaken to investigate the role of rosiglitazone in neuroprotection mediated by GLT-1 following focal cerebral I/R injury in rat. We found that rosiglitazone (2 mg/kg i.p) administered pre- or post-I/R injury significantly improved behavioral outcome and decreased cerebral infarct volume. However, no significant changes were observed in GLT-1 mRNA and protein expression in rosiglitazone-treated rats following 1 hr of ischemia/24 hr of reperfusion (1/24 hr I/R) injury. Interestingly, bioinformatics analysis also does not reveal any PPAR response element on the GLT-1/EAAT2 promoter region. Further rosiglitazone neither increased [(3) H]glutamate uptake in glia-enriched preparations nor caused any change in glutamine synthetase activity. On the other hand, there was a significant (P < 0.05) downregulation in tumor necrosis factor-α and interleukin-1ß gene expression, which were more pronounced in the posttreatment group. The posttreatment with rosiglitazone also significantly reduced the increase in prostaglandin E2 level in the ischemic brain. Therefore, the present findings suggest that the neuroprotective effect of rosiglitazone does not seem to be mediated by modulation of GLT-1 protein expression/activity in a focal cerebral ischemia model. However, the results do provide increasing evidence that the neuroprotective effect may be mediated by its antiinflammatory action.

Anti-stroke profile of thiazolidin-4-one derivatives in focal cerebral ischemia model in rat.

Recently, some PPARγ agonists like pioglitazone, rosiglitazone, and other newer thiazolidine-2, 4-dione (TZD) derivatives have been shown to be neuroprotective in experimental model of cerebral ischemia/reperfusion (I/R) injury. Replacement of active pharmacophore viz: thiazolidine-2,4-dione of these PPARγ agonists with biologically privileged scaffold thiazolidin-4-one derivatives have been synthesized and bioevaluated in focal cerebral ischemia model in rats with an aim to ameliorate cerebral ischemic damage. Of 20 synthesized molecules, three of the substituted compounds (2, 6 and 18) have shown significant (p < 0.001) neuroprotection even much better than rosiglitazone at same dose, when administered 1 h prior to 2/24hrI/R cerebral injury in rats, whereas compounds 10, 15, and 17 also showed significant but moderate effect on most of the parameters used in the study. Moreover, compound 2 and 6 also showed curative potential after 6 h post I/R treatment. The compound 2 has also shown significant effect on glutamate uptake by perhaps enhancing the GLT-1 activity. Thus, the present study indicates that some of the synthesized thiazolidin-4-one substituted PPARγ agonists exhibit better neuroprotection and have potential to ameliorate the ischemic damage. Therefore, this novel class of compounds could be further suitably modified to obtain potent anti-ischemic agents, warranting clinical exploitation.

The neuroprotective effects of NMDAR antagonist, ifenprodil and ASIC1a inhibitor, flurbiprofen on post-ischemic cerebral injury.

Owing to the complex and multifactorial pathology of cerebral stroke, multiple drug therapy had long been advocated by STAIR committee for stroke successful treatment. In this context, we analyzed the effect of Ifenprodil, an NR2b selective NMDAR antagonist and its combination at lower doses with flurbiprofen, a selective ASIC1a inhibitor on rat model of focal cerebral ischemia. We found that the combination produced significant neuroprotective effect as produced by ifenprodil at higher doses, which was evidenced by reduction in infarct volume, neurological deficit and MDA levels. Further, histopathological studies revealed that, the combination not only attenuated the cell damage in striatal regions of ischemic brain, but also significantly inhibited apoptotic cell death, which was more pronounced than monotherapy with ifenprodil or flurbiprofen. Thus, it appears that the combination therapy will be more efficacious in offering neuroprotection on one hand and also lower the risks associated by mono-therapy with ifenprodil at higher doses.

Endoplasmic reticulum stress in brain damage.

The efficient functioning of the ER is indispensable for most of the cellular activities and survival. Disturbances in the physiological functions of the ER result in the activation of a complex set of signaling pathways from the ER to the cytosol and nucleus, and these are collectively known as unfolded protein response (UPR), which is aimed to compensate damage and can eventually trigger cell death if ER stress is severe or persists for a longer period. The precise molecular mechanisms that facilitate this switch in brain damage have yet to be understood completely with multiple potential participants involved. The ER stress-associated cell death pathways have been recognized in the numerous pathophysiological conditions, such as diabetes, hypoxia, ischemia/reperfusion injury, and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and bipolar disorder. Hence, there is an emerging need to study the basic molecular mechanisms of ER stress-mediating multiple cell survival/death signaling pathways. These molecules that regulate the ER stress response would be potential drug targets in brain diseases.

Neuroprotective effect of flurbiprofen in focal cerebral ischemia: the possible role of ASIC1a.

The intracellular calcium overload resulting from glutamate excitotoxicity is considered major determinant for neuronal loss during cerebral ischemia. Moreover, acidosis mediated ASIC1a activation has also shown to promote intracellular calcium overload following ischemic insult. Interestingly, ASIC1a was found to be inhibited by NSAIDs particularly flurbiprofen and ibuprofen, which could be exploited in hypoxic conditions like cerebral ischemia. This prompted us to investigate neuroprotective effect of flurbiprofen, besides its possible downstream signaling mechanism in rodent model of focal cerebral ischemia. The flurbiprofen treatment, 30 min prior to ischemia and 4 h post-reperfusion, afforded significant neuroprotection from ischemic injury as evidenced by reduction in cerebral infarct volume and neurobehavioral deficit. Further, an early calcium dependent rise in levels of nitrite and MDA was also found to be significantly (P < 0.01) reduced in ischemic brain regions following flurbiprofen pretreatment. It also reduced the proteolytic products (SBDPs) caused by ischemic activation of calcium dependent protease calpain. In addition, the ex-vivo studies with flurbiprofen in rat brain synaptoneurosomes inhibited the acid mediated rise in intracellular calcium levels. These studies thus provide neuroprotective profile of flurbiprofen in focal cerebral ischemia with its selective effect on ASIC1a.

Neuroprotective potential of the NF-κB inhibitor peptide IKK-NBD in cerebral ischemia-reperfusion injury.

Inflammation plays an important role in ischemic pathology. NF-κB is a transcription factor that has a crucial role in inflammation and cell survival, but its precise role in the ischemic aftermath is still uncertain. Therefore, we evaluated the effect of intracerebroventricular administration of a highly specific NF-κB inhibitor peptide, IKK-NBD, on transient focal cerebral ischemic injury in rat using middle cerebral artery occlusion model. The assessment of ischemia-induced neurological deficits, alterations in the proinflammatory cytokine IL-1ß level, OX-42 immunoreactivity, changes in blood-brain barrier (BBB) permeability, reactive oxygen species (ROS) production and DNA fragmentation by terminal dUTP nick end labelling (TUNEL) were monitored at 24h post reperfusion following 1h of ischemia after pre-treatment with either 40µg of IKK-NBD or the inactive IKK-NBD peptide, which served as control. Pre-treatment with IKK-NBD peptide significantly ameliorated the cerebral ischemia-induced neurological deficits. Quantification of IL-1ß by ELISA revealed significantly reduced striatal IL-1ß level in IKK-NBD peptide treated rats. The treatment also resulted in reduced staining of microglial OX-42 and significantly reduced extravasation of Evans blue dye, indicating protection of BBB from ischemic insult. These results indicate that specific NF-κB inhibition downplays post-ischemic inflammation. Furthermore, reduction in DNA fragmentation as assessed by TUNEL staining also confirms the neuroprotective effect of IKK-NBD peptide. Thus, it may be inferred that IKK-NBD peptide reduces ischemic brain damage and this can, at least partly, be attributed to reduction in inflammation following ischemic injury.

Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury.

Recently glutamate transporters have emerged as a potential therapeutic target in a wide range of acute and chronic neurological disorders, owing to their novel mode of action. The modulation of GLT-1, a major glutamate transporter has been shown to exert neuroprotection in various models of ischemic injury and motoneuron degeneration. Therefore, an attempt was made to explore its neuroprotective potential in cerebral ischemia/reperfusion injury using ceftriaxone, a GLT-1 modulator. Pre-treatment with ceftriaxone (100mg/kg. i.v) for five days resulted in a significant reduction (P<0.01) in neurological deficit as well as cerebral infarct volume after 1h of ischemia followed by 24h of reperfusion injury. It also caused a significant (P<0.05) upregulation of GLT-1 mRNA, protein and glutamine synthetase (GS) activity. Furthermore, inhibition of ceftriaxone-mediated increased glutamine synthetase activity by dihydrokainate (DHK), a GLT-1 specific inhibitor, confirms the specific effect of ceftriaxone on GLT-1 activity. In addition, ceftriaxone also induced a significant (P<0.01) increase in [(3)H]-glutamate uptake, mediated by GLT-1 in glial enriched preparation, as evidenced by use of DHK and DL-threo-beta-benzyloxyaspartate (DL-TBOA). Thus, the present study provides overwhelming evidence that modulation of GLT-1 protein expression and activity confers neuroprotection in cerebral ischemia/reperfusion injury.

Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats.

The endoplasmic reticulum(ER) stress plays a vital role in mediating ischemic neuronal cell death. However, very little is known about the role of ER stress in mediating pathophysiological reactions to acute brain injuries. An attempt was therefore made to assess the role of cerebral ischemia/reperfusion (I/R) induced ER stress and its modulation on outcome of ischemic insult. Focal cerebral ischemia was induced in rats by middle cerebral artery occlusion (MCAO) for 2 h followed by varying time points of reperfusion. The brain loci specific and time-dependent alterations were seen in the expression pattern of molecular markers, i.e., heat-shock protein 70 (HSP70) for cytoplasmic dysfunction, glucose-regulated protein 78 (GRP78), Caspase-12, C/EBP homologous protein/growth arrest and DNA damage-inducible gene 153 (CHOP/GADD153), activating transcription factor 4 (ATF-4), and Processed X-box protein 1 (xbp1) mRNA for ER dysfunction. Further, histological examinations indicated pronounced brain damage, massive neuronal loss, and DNA fragmentation predominantly in the striatum and cortex. The enhanced expression of GRP78, Caspase-12, CHOP/GADD153, ATF4 and processing of xbp1 mRNA in the affected brain regions clearly indicate the critical involvement of ER-mediated cell death/survival mechanisms and also collectively demonstrated the activation of unfolded protein response (UPR). Moreover, Salubrinal, a selective inhibitor of eIF2alpha dephosphorylation was used to counteract ER stress, which significantly increased the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha), leading to reduced brain damage after I/R injury. Therefore, inhibition of ER stress following I/R injury may be used as key therapeutic target for neuroprotection.

Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.

Parkinson's disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinson's symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD.

Cassane diterpenes from Caesalpinia bonduc.

Three cassane diterpene hemiketals, caesalpinolide-C, caesalpinolide-D, caesalpinolide-E and one cassane furanoditerpene were isolated from Caesalpinia bonduc. The molecular structures were elucidated using NMR spectroscopy in combination with IR, UV and mass spectral data and relative stereochemistries were determined through ROESY correlation. The isolated compounds were tested for their antiproliferative activity against MCF-7 (breast adenocarcinoma), DU145 (prostate carcinoma), C33A (Cervical carcinoma) and Vero (African green monkey kidney fibroblast) cells.

Candesartan improves memory decline in mice: involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin.

The Renin-angiotensin system, besides blood pressure regulation, affects learning and memory as evidenced by improvement of cognition in hypertensive patients being treated with AT1 receptor blockers like candesartan. The present study examined the influence of candesartan on memory impairment induced by intracerebral streptozotocin (IC STZ 0.5 mg/kg) in mice. Candesartan (0.05 mg/kg and 0.1 mg/kg, i.p.) was given for 14 days following IC STZ administration. The dose of 0.1 mg/kg significantly improved latency period in passive avoidance test. Further, treatment with 0.1 mg/kg candesartan for 14 days significantly improved spatial memory in mice in water maze test also. In another group, after memory impairment in mice following IC STZ administration, memory improving effect of a 7 days treatment with 0.1 mg/kg candesartan lasted only for 3 subsequent days in water maze task. IC STZ increased oxidative stress but pretreatment with 0.1 mg/kg candesartan decreased oxidative stress as indicated by a decrease in MDA and increase in GSH. Further, candesartan decreased free radicals as evidenced by flow cytometry. IC STZ affected cholinergic system also by increasing acetylcholine esterase activity that was restored by pretreatment with 0.1 mg/kg candesartan. Locomotor activity and serum glucose level remained unaffected by candesartan treatment. These results suggest that AT1 receptors play a facilitatory role in STZ induced memory deficit and corroborate number of human studies that AT1 receptor blockers can be used therapeutically against cognitive decline in hypertensive patients.

Rare dipeptide and urea derivatives from roots of Moringa oleifera as potential anti-inflammatory and antinociceptive agents.

In the course of our studies on the isolation of bioactive compounds from the roots of Moringa oleifera, a traditional herb in southeast Asia, rare aurantiamide acetate 4 and 1,3-dibenzyl urea 5 have been isolated and characterized. And also, this is the first report of isolation from this genus. Isolated compound inhibited the production of TNF-alpha and IL-2; further compound 5 showed significant analgesic activities in a dose dependant manner. These findings may help in understanding the mechanism of action of this traditional plant leading to control of activated mast cells on inflammatory conditions like arthritis, for which the crude extract has been used.

Spermicidal activity of bivittoside D from Bohadschia vitiensis.

BACKGROUND: A recent revelation about increased susceptibility to HIV by use of nonoxynol-9 (N-9) has called for identification of novel molecules with potent sperm-attenuating activity and lower side-effect profile, as suitable alternatives. The present study was designed to investigate spermicidal activity in Bohadschia vitiensis whole-body extracts followed by isolation and characterization of bioactive molecule. METHODS: Bohadschia vitiensis (Semper) was collected from the Southern Andaman coast of India. Freshly collected marine animals were extracted with methanol. A portion of the crude extract was fractionated into four fractions by macerating with hexane, chloroform, and n-butanol successively. All fractions were evaluated for spermicidal activity. Because maximum activity was localized in the n-butanol soluble fraction, it was chromatographed over a silica gel column, and elution with chloroform-methanol-water (35:10:2, v/v) yielded the major compound bivittoside D (400 mg). Bivittoside D [molecular weight (MW) 1426] is a lanostane triterpenoid with six monosaccharide units. The structure of the compound was established on the basis of physicochemical data, acid hydrolysis of saponin, identification of sugar units and aglycon, melting point, and by comparison with data reported in the literature. RESULTS: The aqueous methanol extract of the Bohadschia vitiensis caused 100% mortality of human sperm at 0.01% concentration in vitro, whereas N-9 (reference control) exhibited an equivalent activity at 0.05%. On further fractionation, activity was localized in n-butanol soluble fraction from which the major compound purified was a lanostane triterpenoid called bivittoside D. Bivittoside D was found to be a more potent spermicide (approximately 2.3 times) than N-9 and killed 100% human sperm at the concentration of 350 muM in approximately 20 sec in vitro. Supravital staining and hypoosmotic swelling test revealed sperm membrane permeabilization by bivittoside D as the major mode of spermicidal action. However, bivittoside D was much safer than N-9 towards normal vaginal flora (Lactobacillus) in vitro, although it affected the viability of HeLa cells like other surfactants. CONCLUSION: Bivittoside D from B. vitiensis can adequately replace N-9 in vaginal contraceptives to make them more vaginally safe and ecofriendly.

New ceramides from the sponge Cinachyra cavernosa.

Two new ceramides 1 and 2, and tetillapyrone 3 have been isolated from the Indian sponge Cinachyra cavernosa. The structures of 1, 2, and 3 were determined by spectroscopic and chemical analyses.

Multifaceted web resources for stroke.

The Internet is an increasingly important tool for stroke survivors, their family members, and health care providers and researchers. An immense amount of information on stroke, ranging from pathophysiology and treatment to poststroke management, is available on the World Wide Web. This article presents lists of Internet search engines related to life science research, web pages of societies working in the field of stroke, and links to websites providing information on treatment, support, and poststroke survival and rehabilitation programs. Policies should be made to promote use of the Internet by patients, caregivers, and researchers working in the field of stroke to encourage improved patient care, communication, and research.

Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities.

Cerebral ischemia/reperfusion (I/R) injury triggers multiple and distinct but overlapping cell signaling pathways, which may lead to cell survival or cell damage. There is overwhelming evidence to suggest that besides necrosis, apoptosis do contributes significantly to the cell death subsequent to I/R injury. Both extrinsic and intrinsic apoptotic pathways play a vital role, and upon initiation, these pathways recruit downstream apoptotic molecules to execute cell death. Caspases and Bcl-2 family members appear to be crucial in regulating multiple apoptotic cell death pathways initiated during I/R. Similarly, inhibitor of apoptosis family of proteins (IAPs), mitogen-activated protein kinases, and newly identified apoptogenic molecules, like second mitochondrial-activated factor/direct IAP-binding protein with low pI (Smac/Diablo), omi/high-temperature requirement serine protease A2 (Omi/HtrA2), X-linked mammalian inhibitor of apoptosis protein-associated factor 1, and apoptosis-inducing factor, have emerged as potent regulators of cellular apoptotic/antiapoptotic machinery. All instances of cell survival/death mechanisms triggered during I/R are multifaceted and interlinked, which ultimately decide the fate of brain cells. Moreover, apoptotic cross-talk between major subcellular organelles suggests that therapeutic strategies should be optimally directed at multiple targets/mechanisms for better therapeutic outcome. Based on the current knowledge, this review briefly focuses I/R injury-induced multiple mechanisms of apoptosis, involving key apoptotic regulators and their emerging roles in orchestrating cell death programme. In addition, we have also highlighted the role of autophagy in modulating cell survival/death during cerebral ischemia. Furthermore, an attempt has been made to provide an encouraging outlook on emerging therapeutic approaches for cerebral ischemia.

Stem cell therapy: a hope for dying hearts.

The restoration of functional myocardium following heart failure still remains a formidable challenge among researchers. Irreversible damage caused by myocardial infarction is followed by left ventricular remodeling. The current pharmacologic and interventional strategies fail to regenerate dead myocardium and are usually insufficient to meet the challenge caused by necrotic cardiac myocytes. There is growing evidence, suggesting that the heart has the ability to regenerate through the activation of resident cardiac stem cells or through the recruitment of a stem cell population from other tissues such as bone marrow. These new findings belie the earlier conception about the poor regenerating ability of myocardial tissue. Stem cell therapy is a promising new approach for myocardial repair. However, it has been limited by the paucity of cell sources for functional human cardiomyocytes. Moreover, cells isolated from different sources exhibit idiosyncratic characteristics including modes of isolation, ease of expansion in culture, proliferative ability, characteristic markers, etc., which are the basis for several technical manipulations to achieve successful engraftment. Clinical trials show some evidence for the successful integration of stem cells of extracardiac origin in adult human heart with an improved functional outcome. This may be attributed to the discrepancies in the methods of detection, study subject selection (early or late post transplantation), presence of inflammation, and false identification of infiltrating leukocytes. This review discusses these issues in a comprehensive manner so that their physiological significance in animal as well as in human studies can be better understood.

One pot synthesis of pyrimidine and bispyrimidine derivatives and their evaluation for anti-inflammatory and analgesic activities.

A number of pyrimidine derivatives (1-10) have been synthesized by condensation of 4-isothiocyanato-4-methylpentan-2-one with furfurylamine, histamine, 1-(3-aminopropyl)imidazole, 1-(3-aminopropyl)-2-pyrrolidinone, 2-aminobenzonitrile and 3-isothiocyanatobutanal with 1-(3-aminopropyl)-2-pyrrolidinone and 2-hydrazinopyridine under different reaction conditions. Various bispyrimidine derivatives (11-15) were obtained by condensation of 4-isothiocyanato-4-methylpentan-2-one with 2,4,8,10-tetraoxaspiro[5,5]undecane3,9-dipropamine (11'), 1,4-bis(3-aminopropyl)piperazine (13'), 3,5-diamino 1,2,4-triazole (15') and 3-isothiocyanatobutanal with 2,4,8,10-tetraoxaspiro[5,5]undecane 3,9-dipropamine, 1,4-bis(3-aminopropyl)piperazine. All these compounds were characterized by correct FT-IR, (1)H NMR, MS and elemental analysis. These compounds were screened for anti-inflammatory and analgesic activities. Anti-inflammatory activity of 3 is comparable while analgesic activity was found to be better than that of standard drug.

Molecular targets in cerebral ischemia for developing novel therapeutics.

Cerebral ischemia (stroke) triggers a complex series of biochemical and molecular mechanisms that impairs the neurologic functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signalling, ionic imbalance, free-radical reactions, etc. These intricate processes lead to activation of signalling mechanisms involving calcium/calmodulin-dependent kinases (CaMKs) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The distribution of these transducers bring them in contact with appropriate molecular targets leading to altered gene expression, e.g. ERK and JNK mediated early gene induction, responsible for activation of cell survival/damaging mechanisms. Moreover, inflammatory reactions initiated at the neurovascular interface and alterations in the dynamic communication between the endothelial cells, astrocytes and neurons are thought to substantially contribute to the pathogenesis of the disease. The damaging mechanisms may proceed through rapid nonspecific cell lysis (necrosis) or by active form of cell demise (apoptosis or necroptosis), depending upon the severity and duration of the ischemic insult. A systematic understanding of these molecular mechanisms with prospect of modulating the chain of events leading to cellular survival/damage may help to generate the potential strategies for neuroprotection. This review briefly covers the current status on the molecular mechanisms of stroke pathophysiology with an endeavour to identify potential molecular targets such as targeting postsynaptic density-95 (PSD-95)/N-methyl-d-aspartate (NMDA) receptor interaction, certain key proteins involved in oxidative stress, CaMKs and MAPKs (ERK, p38 and JNK) signalling, inflammation (cytokines, adhesion molecules, etc.) and cell death pathways (caspases, Bcl-2 family proteins, poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor (AIF), inhibitors of apoptosis proteins (IAPs), heat shock protein 70 (HSP70), receptor interacting protein (RIP), etc., besides targeting directly the genes itself. However, selecting promising targets from various signalling cascades, for drug discovery and development is very challenging, nevertheless such novel approaches may lead to the emergence of new avenues for therapeutic intervention in cerebral ischemia.