Effect of Novel ERβ Agonist in Controlling Neuroinflammation and Apoptosis in Cerebral Ischemia in Rat Model

Anandhakumar, C (2017) Effect of Novel ERβ Agonist in Controlling Neuroinflammation and Apoptosis in Cerebral Ischemia in Rat Model. Masters thesis, PSG College of Pharmacy, Coimbatore.

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Abstract

The present study, administration of novel ER-β agonist at dose of 10mg/kg ameliorated the ischemic damage induced by middle cerebral artery occlusion. However, evidence of a role for ER-β in mediating endogenous E2 neuroprotection against cerebral ischemia is currently lacking, as E2 is fully capable of exerting neuroprotection against cerebral ischemia in ER-β knockout mice (Merchenthaler et al.,2005). Nevertheless, there is evidence that ER-β may have a role in basal neuronal survival, as it has been reported that there is substantial neuronal loss in the brains of ER-β knockout mice at 2 years of age as compared to wild type mice (Wang et al., 2001). Being E2 protective there NCE can be noted on agonist. Several studies have shown that synthetic SERMs, such as tamoxifen, raloxifene or bazedoxifene and natural SERMs, like genistein (Azcoitia et al., 2006), are neuroprotective in vitro and in vivo. Previous reports suggests that both ERα and ERβ regulated pro inflammatory cytokine and chemokine production through E -dependent and E -independent mechanisms (Brown et al., 2010). Estradiol and three ERβ-selective compounds, ERB-041, WAY-202196, and WAY-214156, repressed the expression of these inflammatory genes TNF-α, IL-6, and CSF2 by recruiting the coactivator, SRC-2 has been proved. Estrogen receptors and IGF-I receptors cooperate in neuroprotection in animal models of hippocampal neurodegeneration, Parkinson’s disease and global cerebral ischemia (Azcoitia et al., 1999; Quesada and Micevych, 2004; Garcia-Segura et al., 2006; Mendez et al., 2006). In addition, IGF-I receptor and estrogen receptor activation synergistically increase the activity of the kinase Akt and coordinately regulate protection from neurotoxicity downstream of Akt which further activates glycogen synthase kinase 3β (GSK3β) (Cardona- Gomez et al., 2004). Administration of novel ER-β agonist to MCAo occluded rats did not alter the GSK3β/Akt pathway. In a recent study that the silencing of hippocampal ER β - increased inflammasome activation; whereas periodic ER- β agonist treatment reduced the activation of the inflammasome, consistent with decreased processing of IL- 1β(de Rivero Vaccari et al.,2016). Estrogens can also inhibit expression of pro-inflammatory cytokines such as IL-1β and TNF-α in primary astrocytes following LPS exposure (Lewis et al., 2008). In this study, novel ER β agonist down regulated the brain IL-1β and TNF-α level suggesting their role in controlling neuro inflammation in cerebral ischemic condition. Caspase-3, the final executioner of apoptotic cell death mechanism, is a substrate of calpain and it becomes active following degradation by calpain, and therefore, up regulated calpain is expected to activate caspase-3 in the injured tissue (Gao and Dou.,2000). In our study treatment of novel ER β agonist reduced the caspase 3 activity in MCAo rats. The selective ERα agonist (propylpyrazole triol, PPT) and ERβ agonist (diarylpropionitrile; DPN) are supposed to show similar neuroprotective actions in culture studies. But a previous report showed higher neuroprotective potential of the ERα agonist PPT than the ERβ agonist DPN (Behl et al., 1995). Some other investigations showed that both PPT and DPN can provide neuroprotection against glutamate toxicity by increasing the expression of the anti- apoptotic Bcl-2 protein and also modulating the stress kinase signaling pathways (Zhao et al., 2007). In this study, anti-apoptotic protein bcl2 level were increased and proapoptotic protein levels were reduced on administration of novel ER β agonist to MCAo rats. SUMMARY & CONCLUSION: The objective of the study is to asses the behavioural functions of ER-β stimulation in cerebral ischemic condition using novel NCEs.  To evaluate the mechanism of neuroprotective activity of ER-β agonist in cerebral ischemia by exploring the anti-inflammatory pathways.  MCAo was induced by occluding middle cerebral artery under anesthetic condtions and the behavaioural parameters were studied after 24 hrs and on 7th day.  ER-β agonist CMU, CUE (10mg/kg) has been assessed for their neuroprotective action. The behavioural parameters include measurement of neurogical deficit through grip strength measurement, anxiety beahviour in open feild and elevated plus maze tests. Inducement of MCAo in rats have shown decreased locomtor activity, exploratory, rearing, grooming behaviours, indicates inducement of cerebral ischemia have resulted in anxiogenic behaviour. Post ischemic administration of CMU, CUE (10mg/kg) significantly attenuated the behavioural in MCAo rats as observed by increased locomotor activity, exploratory & grooming behavious, grip strength.  Post ischemic administration of CMU, CUE (10mg/kg) significantly reduced the IL-1β, TNF- α and caspase activity. CUE (10mg/kg) significantly reduced the pro apoptotic Bax & anti apoptotic Bcl2 levels. Novel ER-β agonist has shown neuroprotective effect by downregulating neuro inflammation and attenuating apoptotic pathway.

Item Type: Thesis (Masters)
Uncontrolled Keywords: Novel ERβ ; Agonist ; Controlling Neuroinflammation ; Apoptosis ; Cerebral Ischemia ; Rat Model
Subjects: PHARMACY > Pharmacology
Depositing User: Ravindran C
Date Deposited: 08 Jan 2018 06:01
Last Modified: 08 Jan 2018 06:01
URI: http://repository-tnmgrmu.ac.in/id/eprint/5359

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