Pharmacodynamic Evaluation of Oral Estradiol Nanoparticles in Estrogen Deficient (Ovariectomized) High-Fat Diet Induced Hyperlipidemic Rat Model

Mittal, Gaurav; Godugu, Chandraiah; Ramarao, P.; Kumar, M. N. V. Ravi

doi:10.1007/s11095-008-9725-x

Cited by 17 publications

(14 citation statements)

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“…We also monitored the physiological parameters during surgery such as heart rate, respiratory rate and blood pressure. Ovariectomy was performed as described previously (Mittal et al ., ). Female rats were then randomly divided into six groups and were fed on respective diets for model development (Figure ).…”

Section: Methodsmentioning

confidence: 97%

17‐β Oestradiol prevents cardiovascular dysfunction in post‐menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation

Bendale

Karpe

Chhabra

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEOestrogen therapy is known to induce cardioprotection in post-menopausal metabolic syndrome (PMS). Hence, we investigated the effect of 17-β oestradiol (E2) on functional responses to angiotensin II and cardiovascular dysfunction in a rat model of PMS. EXPERIMENTAL APPROACHPMS was induced in ovariectomized rats by feeding a high-fat diet for 10 weeks. Isometric tension responses of aortic rings to angiotensin II were recorded using an isometric force transducer. TUNEL assay and immunoblotting was performed to assess apoptosis and protein expression respectively in PMS. KEY RESULTSEndothelial dysfunction in PMS was characterized by enhanced angiotensin II-induced contractile responses and impaired endothelial dependent vasodilatation. This was associated with an increased protein expression of AT1 receptors in the aorta and heart in PMS. PMS induced cardiac apoptosis by activating Bax and PARP protein expression. These changes were associated with a down-regulation in the expression of silent information regulation 2 homologue (SIRT1)/P-AMP-activated PK (AMPK) and increased H3 acetylation in aorta and heart. E2 partially suppressed angiotensin II-induced contractions, restored the protein expression of SIRT1/P-AMPK and suppressed H3 acetylation. The role of SIRT1/AMPK was further highlighted by administration of sirtinol and compound C (ex vivo), which enhanced angiotensin II contractile responses and ablated the protective effect of E2 on PMS. CONCLUSION AND IMPLICATIONSOur results provide novel mechanisms for PMS-induced cardiovascular dysfunction involving SIRT1/AMPK/ histone H3 acetylation, which was prevented by E2. The study suggests that therapies targeting SIRT1/AMPK/epigenetic modifications may be beneficial in reducing the risk of cardiovascular disorders. AbbreviationsAMPK, AMP-activated PK; Ang II, angiotensin II; E2, 17-β oestradiol; PMS, post-menopausal metabolic syndrome; SIRT1, silent information regulation 2 homologue BJP British Journal of Pharmacology

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Section: Methodsmentioning

confidence: 97%

17‐β Oestradiol prevents cardiovascular dysfunction in post‐menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation

Bendale

Karpe

Chhabra

et al. 2013

British J Pharmacology

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“…Additionally, following oral administration, E2 PLGA formulations of varying molecular weight (14,500, 45,000 and 213,000 Da) and varying lactide to glycolide ratios (50:50, 65:35) each showed detectable levels of E2 5–11 days after administration, which was significantly longer compared to the dose matched free E2 oral delivery, with detectable levels seen for only 1 day after administration 58 . In a high-fat induced hyperlipidemic rat model, E2 PLGA treatment administered orally every 3 days for 2 weeks significantly reduced body weight compared to controls, whereas a daily oral administration of an E2 suspension did not have a significant effect on body weight 56 . On the other hand, the E2 PLGA treatment in an AD model was effective at preventing amyloid beta plaque formation, but no significant benefit was seen between orally administered E2 PLGA versus E2 suspension treatment 55 .…”

Section: E2 Delivery Using Plga Mncsmentioning

confidence: 85%

“…E2 PLGA MNCs have been studied most commonly in the context of oral or transdermal administration. For instance, Dr. Kumar’s laboratory has analyzed the pharmacokinetics of E2 PLGA following oral administration as well as the effects of E2 PLGA oral treatment in a high-fat induced hyperlipidemic rat model and in an AD rat model 55,56,57,58 . Following 100 ug/kg E2 oral administration, they showed that E2 PLGA treatment resulted in a maximum E2 plasma level of 85 pg/ml at 24 hours, whereas E2 suspension resulted in a maximum E2 plasma level of 102 pg/ml at 4 hours 57 .…”

Section: E2 Delivery Using Plga Mncsmentioning

confidence: 99%

“…When tested in preclinical models of disease, E2 PLGA treatments were able to produce therapeutic effects that either enhanced or were at least equivalent to that of free E2 treatment 55,56,63 . Taken together, these preclinical studies provide initial therapeutic evidence for the use of E2 PLGA MNCs to treat different symptoms.…”

Section: E2 Delivery Using Plga Mncsmentioning

confidence: 99%

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Engineering poly(lactic-co-glycolic acid) (PLGA) micro- and nano-carriers for Controlled Delivery of 17β-Estradiol

2017

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With menopause, circulating levels of 17β-estradiol (E2) markedly decrease. E2-based hormone therapy is prescribed to alleviate symptoms associated with menopause. E2 is also recognized for its beneficial effects in the central nervous system (CNS), such as enhanced cognitive function following abrupt hormonal loss associated with ovariectomy. For women with an intact uterus, an opposing progestogen component is required to decrease the risk of developing endometrial hyperplasia. While adding an opposing progestogen attenuates these detrimental effects on the uterus, it can attenuate the beneficial effects of E2 in the CNS. Poly (lactic-co-glycolic acid) (PLGA) micro- and nano- carriers (MNCs) have been heavily investigated for their ability to enhance the therapeutic activity of hydrophobic agents following exogenous administration, including E2. Multiple PLGA MNC formulation parameters, such as composition, molecular weight, and type of solvent used, can be altered to systematically manipulate the pharmacokinetic and pharmacodynamic profiles of encapsulated agents. Thus, there is an opportunity to enhance the therapeutic activity of E2 in the CNS through controlled delivery from PLGA MNCs. The aim of this review is to consider the fate of exogenously administered E2 and discuss how PLGA MNCs and route of administration can be used as strategies for controlled E2 delivery.

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“…Among the approaches for exploiting nanotechnology developments in medicine, several nanoparticulates offer certain unique advantages as pharmaceutical delivery systems and image enhancement agents (West & Halas, 2000;LaVan et al, 2002). Varieties of nanoparticles (Sahoo & Labhasetwar, 2003) such as different polymeric and liposomes, metal nanoparticles, micelles, Mittal et al (2009) quantum dots, microcapsules, dendrimers, cells, cell ghosts, lipoproteins and many different nanoassemblies are available. All these nanoparticles can play a main role in diagnosis and therapy.…”

Section: Nanoparticle Carrier Systemmentioning

confidence: 99%

Nanoparticulate carrier system: a novel treatment approach for hyperlipidemia

2014

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Hyperlipidemia is a prevailing risk factor that leads to development and progression of atherosclerosis and consequently cardiovascular diseases. Several antihyperlipidemic drugs are having various disadvantages such as low water solubility and poor bioavailabilty due to presystemic gastrointestinal clearance. Thus, there is a considerable need for the development of efficient delivery methods and carriers. This review focuses on the importance and role of various nanoparticulate systems as carrier for antihyperlipidemic drugs in the treatment of hyperlipidemia. Some nanoparticle technology-based products are approved by FDA for effective treatment of hyperlipidemia, namely Tricor® by Abbott Laboratories (Chicago, IL, USA) and Triglide® by Skye Pharma (London, UK). Efforts to address each of these issues are going on, and should remain the focus on the future studies and look forward to many more clinical products in the future.

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Pharmacodynamic Evaluation of Oral Estradiol Nanoparticles in Estrogen Deficient (Ovariectomized) High-Fat Diet Induced Hyperlipidemic Rat Model

Abstract: Together, these results demonstrate the ability of nanoparticles in improving oral bioavailability/efficacy of estradiol.

Cited by 17 publications

References 40 publications

17‐β Oestradiol prevents cardiovascular dysfunction in post‐menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation

17‐β Oestradiol prevents cardiovascular dysfunction in post‐menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation

Engineering poly(lactic-co-glycolic acid) (PLGA) micro- and nano-carriers for Controlled Delivery of 17β-Estradiol

Nanoparticulate carrier system: a novel treatment approach for hyperlipidemia

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