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Reverse transcription-polymerase chain reaction analysis of the FP receptor gene in human ciliary bodies. ( a ) The location of PCR products of the correct size for known wild-type FP receptor, abbreviated as WT-FP, and FP receptor variants, abbreviated as AltFP, are indicated by arrows. Sequencing analysis showed that the band of altFP contains multiple FP receptor variants. ( b ) The black bars represent the coding sequence for the wild-type FP receptor. There are five additional exons generated by mRNA alternative splicing, located between exon 2 and exon 3 and indicated as exon A, exon B, exon C, exon D and exon E.
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A prostamide analogue, bimatoprost, has been shown to be effective in reducing intraocular pressure, but its precise mechanism of action remains unclear. Hence, to elucidate the molecular mechanisms of this effect of bimatoprost, we focused on pharmacologically characterizing prostaglandin FP receptor (FP) and FP receptor variant (altFP) complexes....
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Citations
... In contrast to arachidonic acid-derived prostaglandin F 2α , PGF 2α EA and its synthetic analog bimatoprost (Bim) have been suggested to owe both their intra-ocular pressure-lowering and anti-adipogenic effects to the activation of a heterodimeric receptor consisting of the canonical prostaglandin F 2α receptor and an alternately spliced prostaglandin F 2α receptor alt4 variant that is still not completely characterized (21,(39)(40)(41)(42)(43)(44)(45). However, like prostaglandin F 2α , Bim and PGF 2α EA inhibit the early adipogenic program, by reducing the Pparg and CCAAT enhancer-binding protein alpha (Cebpa) gene expression downstream of mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ ERK) signaling (21,46). ...
White adipose tissue regulation is key to metabolic health, yet still perplexing. The chief endocannabinoid anandamide metabolite, prostaglandin F2α ethanolamide (PGF2αEA), inhibits adipogenesis, that is, the formation of mature adipocytes. We observed that adipocyte progenitor cells—preadipocytes—following treatment with PGF2αEA yielded larger pellet sizes. Thus, we hypothesized that PGF2αEA might augment preadipocyte proliferation. Cell viability MTT and crystal violet assays, cell counting, and 5-bromo-2′-deoxyuridine incorporation in cell proliferation ELISA analyses confirmed our prediction. Additionally, we discovered that PGF2αEA promotes cell cycle progression through suppression of the expression of cell cycle inhibitors, p21 and p27, as shown by flow cytometry and qPCR. Enticingly, concentrations of this compound that showed no visible effect on cell proliferation or basal transcriptional activity of peroxisome proliferator-activated receptor gamma could, in contrast, reverse the anti-proliferative and peroxisome proliferator-activated receptor gamma-transcription activating effects of rosiglitazone (Rosi). MTT and luciferase reporter examinations supported this finding. The PGF2αEA pharmaceutical analog, bimatoprost, was also investigated and showed very similar effects. Importantly, we suggest the implication of the mitogen-activated protein kinase pathway in these effects, as they were blocked by the selective mitogen-activated protein kinase kinase inhibitor, PD98059. We propose that PGF2αEA is a pivotal regulator of white adipose tissue plasticity, acting as a regulator of the preadipocyte pool in adipose tissue.
... The possible mechanisms of PGAs include the relaxation of ciliary smooth muscles, the alteration of cytoskeletal, and the remodeling of the extracellular matrix of the uveoscleral pathway [10]. Although often broadly categorized into the PGA class, bimatoprost is actually a synthetic prostamide, which is structurally distinct from other prostaglandin analogues [11]. ...
Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP), and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). A total of 57 (41%) eyes were under three or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. The mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg, respectively. Significant differences in tIOP were found between heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (p = 0.031). The MD values presented significant differences between wildtype rs3766355 (−2 ± 2.2 dB), HT (−3.87 ± 4 dB), and HM carriers (−9.37 ± 9.51 dB) (p = 0.009). Significant differences were also observed between the MD in wildtype rs3753380 (−6.1 ± 8.67 dB), HT (−9.02 ± 8.63 dB), and HM carriers (−9.51 ± 7.44 dB) (p = 0.017). Patients carrying the variant rs3766355 in HM or HT presented clinically-significantly higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, and the more alleles that were affected, the worse the MD value, meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles.
... While serving only a limited role in colon inflammation, prostaglandin D 2 ethanolamine induces skin cancer apoptosis independent of the putative DP receptors, but the precise mechanism remains unclear [259]. Perhaps the most well-established endogenous prostamide, prostaglandin F 2 α ethanolamine exerts minimal activity through the prostaglandin F 2α receptor and instead likely acts through an FP receptor variant [260]. A structural analogue of prostaglandin F 2α ethanolamine, Bimatoprost is an FDA-approved drug marketed under the name Lumigan ® (Allergan) for reducing intraocular pressure as a treatment for glaucoma [261], and a sustained-release formulation of Bimatoprost is currently undergoing testing in Phase I/II clinical trials [262]. ...
Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide. Since the discovery of Δ9-tetrahydrocannabinol (THC) as the primary psychoactive component of cannabis over 50 years ago, substantial effort has been directed toward detection of endogenous mediators of cannabinoid activity. The discovery of anandamide and 2-arachidonoylglycerol as two endogenous lipid mediators of cannabinoid-like effects (endocannabinoids) has inspired exponential growth in our understanding of this essential pathway, as well as the pathological conditions that result from dysregulated endocannabinoid signaling. This review examines current knowledge of the endocannabinoid system including metabolic enzymes involved in biosynthesis and degradation and their receptors, and evaluates potential druggable targets for therapeutic intervention.
... BIM-A is an acid form of prost-type PG analogues derived from PGF2α by the addition of a phenyl base at C-17 that is important for binding to the prostanoid FP receptor, and conservation of the C-15 hydroxyl base (Taketani, Yamagishi, Fujishiro, Igarashi, Sakata & Aihara, 2014). BIM-A binds directly to a dimer prostamide receptor, which is composed of the FP receptor and an FP receptor splice variant (Liang et al., 2008). This suggests that BIM-A induced DUES may reasonably be related to FP receptors. ...
... BIM is a prostamide type, and its C-terminal of PGF2α is replaced by ethylamide. In contrast, BIM-A directly binds to a dimer prostamide receptor, which is composed of the FP receptor and an FP receptor splice variant 25 . Based upon these observations, suppression of adipogenesis by PGs may be related to their FP receptors. ...
To establish a deepening of the upper eyelid sulcus (DUES) model that can be induced by prostaglandin (PG) analogues, a three-dimension (3D) tissue culture was employed. Upon adipogenesis of the 3T3-L1 organoid, the effects of either Bimatoprost acid (BIM-A), or PGF2α were examined. During the adipogenesis, organoid size, lipid staining by BODIPY and expression of the extracellular matrix (ECM) by immunocytochemistry and/or quantitative PCR were employed. The size of the organoid increased remarkably during the adipogenesis, while such increases were significantly inhibited by the presence of PGF2α or BIM-A. BODIPY positive lipid-laden cells significantly increased during the adipogenesis, while in contrast they were greatly suppressed by the presence of PGF2α. Characteristic and spatial changes in ECM expressions observed upon adipogenesis were greatly modified by the presence of PGs. Our present study using a 3D tissue culture may be a suitable strategy toward understanding disease etiology of DUES.
... The major receptor for bimatoprost and prostamide F2αis the prostamide receptor, which is a variant form of the FP receptor (25). It has been pharmacologically identi ed by speci c receptor antagonists that block its actions in primates in vivo, but not those of FP agonists. ...
Background
Bimatoprost negatively regulates adipogenesis in vitro and likely participates in a negative feedback loop on anandamide-induced adipogenesis. Here, we investigate the broader metabolic effects of bimatoprost action in vivo in rats under both normal state and obesity-inducing conditions.
Methods
Male Sprague Dawley rats were a fed standard chow (SC) diet in conjunction with dermally applied bimatoprost treatment for a period of 9–10 weeks. Body weight gain, energy expenditure, food intake, and hormones associated with satiety were measured. Gastric emptying was also separately evaluated. In obesity-promoting diet studies, rats were fed a cafeteria diet (CAF) and gross weight, fat accumulation in SQ, visceral fat and liver was evaluated together with standard serum chemistry.
Results
Chronic bimatoprost administration attenuated weight gain in rats fed either standard or obesity-promoting diets over a 9–10 weeks. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Additionally, SQ and visceral fat mass was distinctly affected by treatment. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels.
Conclusions
These findings suggest that bimatoprost (and possibly prostamide F2α) regulates energy homeostasis through actions on dietary intake. These actions likely counteract the metabolic actions of anandamide through the endocannabinoid system potentially revealing a new pathway that could be exploited for therapeutic development.
... 51 Bimatoprost is less efficiently hydrolyzed by corneal amidases. 51 Both the intact bimatoprost molecule and bimatoprost free acid have biological activity [52][53][54] and are present in ocular tissues after topical bimatoprost administration, 51 and both the intact bimatoprost molecule and the free acid have been proposed to contribute to the IOP-lowering effects of topical bimatoprost. 51,[55][56][57][58] The PGAs lower IOP by enhancing aqueous outflow, 59 and latanoprost, bimatoprost, and travoprost consistently have been reported to increase outflow through the uveoscleral pathway. ...
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.
... Anandamide and 2-AG can be metabolized via oxidation by cyclooxygenase 2 (ref. 49 ) and the end products (prostaglandin ethanolamides and prostaglandin glycerol esters) act at receptors other than cannabinoid and prostanoid receptors 50,51 . Furthermore, 2-AG can be phosphorylated to the corresponding lysophosphatidic acid, which acts at its own receptors 52 . ...
Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system - known as the endocannabinoidome - that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.
... In fact, it has been postulated that the effects of prostaglandin-ethanolamides are actually mediated by receptors that are specific to this subclass of prostaglandins [29]. Indeed, an alternatively spliced FP receptor was found to be responsible for the activity of PGF 2α -EA [64]. Unfortunately, receptors for PGD 2 -EA have not been identified. ...
The combined incidence of melanoma and non-melanoma skin cancer (NMSC) is greater than the incidence of all other malignancies in the US. Previously, we demonstrated that the endocannabinoid, arachidonoyl-ethanolamide (AEA), was a potent inducer of apoptosis in NMSC. The metabolism of AEA to the prostaglandin, PGD 2 -EA, was a prerequisite for AEA cytotoxicity. However, the mechanism of PGD 2 -EA cell death has not been clearly defined. In the present study, we report that PGD 2 -EA causes apoptosis in melanoma and NMSC cells. Mass spectrometry analysis revealed that PGD 2 -EA was dehydrated to three J-series prostaglandins; PGJ 2 -EA, Δ ¹² PGJ 2 -EA, and 15deoxy,Δ12,14 PGJ 2 -EA. PGD 2 -EA inhibited the antioxidant activity of glutathione and thioredoxin which then caused oxidative stress. This increase in oxidative stress was accompanied by the activation of endoplasmic reticulum (ER) stress and apoptosis. The effect of PGD 2 -EA was independent of DP1, DP2, and PPARγ receptors suggesting that PGD 2 -EA cytotoxicity was mediated by its metabolic product, 15dPGJ 2 -EA.
... Bimatoprost is a prostaglandin F2 alpha (PGF2a) analogue used as topical therapy for glaucoma, which binds to a prostamide receptor composed of a heterodimer complex of prostanoid F (FP) receptor and its splice variants. 11 In metabolically active tissue in vivo, bimatoprost also undergoes conversion into bimatoprost acid by tissue esterases, which then can bind the FP receptor itself and initiates a variety of intracellular signaling cascades. [11][12][13] Interestingly, long-term use of prostaglandin (PG) analogues has been shown to lead to PG-associated periorbitopathy (PAP), which is characterized by reversible atrophy of periorbital tissues, including orbital adipocytes. ...
... 11 In metabolically active tissue in vivo, bimatoprost also undergoes conversion into bimatoprost acid by tissue esterases, which then can bind the FP receptor itself and initiates a variety of intracellular signaling cascades. [11][12][13] Interestingly, long-term use of prostaglandin (PG) analogues has been shown to lead to PG-associated periorbitopathy (PAP), which is characterized by reversible atrophy of periorbital tissues, including orbital adipocytes. 14,15 While the molecular mechanism behind PAP remains incompletely elucidated, studies suggest that PG analogues, such as bimatoprost, decrease human preadipocyte differentiation and intracellular lipid accumulation by inhibiting the PPARc pathway. ...
... In vivo, tissue esterase can degrade bimatoprost into bimatoprost acid, which then binds the prostanoid FP receptor. 11 Previous studies have demonstrated that activation of the prostanoid FP receptor by bimatoprost turns on the PI3K/Akt and MAPK/ERK pathways in murine myoblasts and retinal ganglion cells, respectively. 20 In feline iris sphincter cells, bimatoprost has been noted to selectively stimulate the p38 MAPK pathway, as well as intracellular calcium signaling. ...
Purpose:
We characterize the effect of bimatoprost on orbital adipose tissue in thyroid-associated orbitopathy (TAO) with clinicopathologic correlation.
Methods:
Orbital adipose-derived stem cells (OASCs) from types 1 and 2 TAO and control patients with and without exposure to 1 μm bimatoprost were examined via immunohistochemistry, RT-PCR, and Western blot for cell viability, migration capacity, lipid content, adipocyte morphology, mitochondrial content, and levels of adipogenic markers. A retrospective chart review was performed for clinicopathologic correlation. In mice, optical coherence tomography and pattern electroretinography were performed at baseline and at 1 month following a retrobulbar injection of bimatoprost, followed by orbital exenteration for histopathologic examination.
Results:
Types 1 and 2 TAO-derived cells had a significantly higher migration capacity and lipid content than those of healthy controls. With the addition of bimatoprost, types 1 and 2 TAO and control adipocytes exhibited a significant decrease in lipid content with morphologic transformation into smaller and multilocular lipid droplets, and an increase in mitochondrial load and UCP-1 expression consistent with an increase in brown adipose tissue turnover. Retrobulbar injection of bimatoprost in mice did not alter the gross morphology, retinal thickness, or ganglion cell function in vivo.
Conclusions:
Bimatoprost inhibits adipogenesis in OASCs and upregulates pathways involved in the browning of adipocytes. Furthermore, retrobulbar injection of bimatoprost is tolerated without immediate adverse effects in mice. Our results suggest a potential future application of prostaglandin analogues in the treatment of TAO.
