Saroglitazar Research Articles

Saroglitazar Enhances Memory Functions and Adult Neurogenesis via Up-Regulation of Wnt/β Catenin Signaling in the Rat Model of Dementia.

Peroxisome proliferator-activated receptors (PPARs) have emerged as a promising target for the treatment of various neurodegenerative disorders. Studies have shown that both PPAR α & γ individually modulate various pathophysiological events like neuroinflammation and insulin resistance, which are known to variedly affect neurogenesis. Our study aimed to evaluate the effect of saroglitazar (SGZR), a dual PPAR agonist, on adult neurogenesis and spatial learning and memory, in intracerebroventricular streptozotocin (ICV STZ)-induced dementia in rats. We have found that SGZR at the dose of 4 mg/kg per oral showed significant improvement in learning and memory compared to ICV STZ-treated rats. A substantial increase in neurogenesis was observed in the subventricular zone (SVZ) and the dentate gyrus (DG), as indicated by an increase in the number of 5-bromo-2'-deoxyuridine (BrdU)+ cells, BrdU+ nestin+ cells, and doublecortin (DCX)+cells. Treatment with SGZR also decreased the active form of glycogen synthase kinase 3β (GSK3β) and hence enhanced the nuclear translocation of the β-catenin. Enhanced expression of Wnt transcription factors and target genes indicates that the up-regulation of Wnt signaling might be involved in the observed increase in neurogenesis. Hence, it can be concluded that the SGZR enhances memory functions and adult neurogenesis via the upregulation of Wnt β-catenin signaling in ICV STZ-treated rats.

Saroglitazar, a PPAR α/γ agonist alleviates 3-Nitropropionic acid induced neurotoxicity in rats: Unveiling the underlying mechanisms

Saroglitazar (SGZ), a peroxisomal proliferated activated receptor α/γ agonist showed neuroprotective effects in various neurodegenerative disorders like Alzheimer’s and Parkinson’s. However, no studies were performed on Huntington’s, so the goal of the current study is to examine the effect of SGZ on Huntington’s disease like symptoms induced by 3-Nitropropionic acid. In this protocol, twenty-four rats were divided into four groups, each group consisting of 6 animals. Group 1: The control group received 1 % CMC 10 mg/kg, p.o. for 14 days. Groups 2, 3, and 4 received 3-NP 15 mg/kg, i.p. from Day 1 to Day 7. Groups 3 and 4 received SGZ 5 mg/kg, p.o. and 10 mg/kg, p.o. respectively once daily from day 1 to day 14. Various behavioral tests like OFT, rotarod, hanging wire, narrow beam walk, MWM, and Y-maze were performed. On day-15, the animals were euthanised by cervical dislocation and brain sample were isolated for biochemical and histopathological analysis. Administration of 3-NP showed a significant decrease in motor coordination and cognitive function. Furthermore, 3-NP altered the activity of acetylcholinesterase, anti-oxidant enzymes, Nrf-2, NF-κB, BDNF, CREB levels, and histological features. However, treatment with SGZ showed ameliorative effects in the 3-NP induced neurotoxicity via PPAR α/γ pathway by reducing motor dysfunction, memory impairment, cholinesterase levels, oxidative stress, neuroinflammation. It also enhanced the levels of Nrf-2, BDNF, and CREB expression and improved histological features. In conclusion, treatment with Saroglitazar attenuated Huntington’s disease-like symptoms in rats which are induced by 3-NP via activation of PPAR α/γ pathway.

Indigenous wisdom of a Kwatha to treat NASH: An insight into the mechanism

Ethnopharmacological relevanceNonalcoholic fatty liver disease (NAFLD) is the most common severe liver disease globally, progressing further into nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Vasaguduchyadi Kwatha (VK) is an Ayurvedic formulation traditionally used to treat liver diseases and other metabolic complications. This study is an ethnopharmacological approach to unravel this indigenous remedy. Aim of the studyWe aimed to discover the probable mechanism of action of VK against NASH in this study, using network pharmacology, molecular docking, in vitro study, and preclinical investigation. Methods and resultsAmong the 55 components identified, 10 were confirmed based on mass, elution charecteristics, MS/MS analysis data, and fragmentation rules. Computational study indicated 92 targets involved in the central pathways of NASH, out of which only 15 targets and 9 VK constituents have significant docking scores. In vitro and in vivo analysis results showed that VK significantly reduces weight gain and improves insulin sensitivity, dyslipidemia, steatohepatitis and overall histological features of NASH compared to saroglitazar (SGZR). ConclusionOur detailed study yielded three signalling pathways related to NASH on which VK has maximum effect, bringing up a probable alternative treatment for NASH.

Suppression of TGF-β/Smad3 signaling pathway by Capparis spinosa and quercetin in a rat model of nonalcoholic steatohepatitis.

Liver diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), pose significant global public health challenges. This study investigates the therapeutic effects of quercetin (QC), Capparis spinosa (CS), a QC and CS combination, and Saroglitazar (SARO) on NASH in a Wistar rat model. NASH was induced by a 42-day high-fat diet regimen in male Wistar rats. Post-induction, rats were divided into five groups receiving SARO, QC, CS, and CS+QC combination. We monitored changes in liver and body weights and evaluated the expression of genes associated with fatty acid biosynthesis (e.g., ACC and FAS), β-oxidation (e.g., CPT1, PPAR α), inflammation (e.g., TNF-α and IL-6), and fibrosis (e.g., TGF-β and COL1A), as well as protein expression levels of p-Smad2/3 and p-Smad3. Treatment with QC+CS significantly decreased liver weight, body mass gain, and liver triglyceride (TG) compared to other treatments. The QC and CS combined therapy also resulted in a greater normalization of hepatic enzymatic activities, including decreases in ALT and AST levels, coupled with improvements in lipid profile indicated by decreased LDL-C and increased HDL-C concentrations, as compared to SARO and QC alone. Furthermore, this combined treatment significantly down-regulated the expression of TGF-β, TNF-α, IL-6 genes, and Smad2/3 and Smad3 protein levels. Our study demonstrates that an interactive effect between QC and CS can effectively reduce liver fibrosis and steatosis by inhibiting the TGF-β/Smad3 signaling pathway in a diet-induced model of nonalcoholic steatohepatitis and fibrosis in rats.

Saroglitazar mitigated NASH-associated hepatic injury in dexamethasone-treated rats via modulating autophagy, apoptosis, and necroptosis

This study aimed to evaluate the possible ameliorative effects of saroglitazar (SAR) on aspects of hepatic injury in dexamethasone (DEX)-induced nonalcoholic steatohepatitis (NASH) in rats.Wistar rats received SAR (2 or 4 mg/kg/day, orally) or metformin (MET, 500 mg/kg/day, orally) for one week before and concurrently with DEX administration (8 mg/kg/day, i.p., for 6 days. Control and drug control groups received vehicle or the higher dose of SAR, respectively. At the end of the experiment, an oral glucose tolerance test (OGTT) was conducted, serum hepatic function parameters and lipid profile were assessed, and hepatic histological changes were evaluated. Moreover, hepatic p-Akt/Akt ratios, malondialdehyde (MDA) content, SREBP-1, FOXO1, LC3, cleaved caspase-3, and p-MLKL protein levels were determined. Furthermore, hepatic immunohistochemical expressions of FOXO1, caspase-3, Bcl-2, LC3, and P62 were examined.SAR (mainly at 4 mg/kg/day) significantly improved Area under the OGTT curve (P < 0.0001), hepatic function parameters, lipid profile, and hepatic histopathological features in DEX-administered rats. Moreover, SAR significantly attenuated DEX-induced increases in hepatic MDA content (P < 0.05), SREBP-1 levels (P < 0.0001), and nuclear FOXO1, caspase-3, LC3, P62, and p-MLKL protein expressions (P < 0.0001). Furthermore, SAR significantly enhanced hepatic p-Akt/Akt ratio and Bcl-2 protein expression in DEX-administered rats (P < 0.0001). The higher dose of SAR showed greater hepatoprotective effects compared to its corresponding lower dose and MET in most assessments, approaching levels similar to the control group.SAR mitigated hepatic injury associated with DEX-induced NASH in rats, suggesting it might be a potential hepatoprotective drug for patients with or at high risk of NASH.

Resveratrol and Saroglitazar: A Promising Combination for Targeting TGF-β/Smad3 Signaling and Attenuating Inflammatory Response in Nonalcoholic Steatohepatitis in Rats

Background: This study aimed to investigate the combined effects of resveratrol (RES) and saroglitazar (SARO) on a high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in a rat model. Methods: In this animal study, rats were treated with RES, SARO, or a combination of both. Male rats were fed with an HFD to induce nonalcoholic steatohepatitis (NASH) and then divided into 4 groups: RES treatment, SARO treatment, combined RES and SARO treatment, and no treatment. Various parameters were measured, including body and liver weight, liver enzymes, gene expression of inflammatory markers and reactive oxygen species (ROS), protein expression levels of transforming growth factor-beta (TGF-β) and p-Smad3, and liver histology. Results: The combination of RES and SARO significantly reduced blood and hepatic lipids, attenuated weight gain, and decreased inflammatory cytokine production in a NAFLD study. The combination diminished hepatic lipid accumulation, oxidative stress, and TGF-β1 expression, suggesting antifibrotic effects. Histological evaluations showed antisteatotic and antifibrotic outcomes of the combined treatment. Improved glycemic index, blood lipids, and reduced NASH indicators (i.e., aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were observed after 6 weeks. The treatment also decreased ROS and NOX family expression, lessening oxidative stress. The inhibition of the TGF-β-Smad3 pathway in HFD-induced rats resulted in reduced NASH (P &lt; 0.05). Conclusions: The results indicated that the group receiving the combination of RES and SARO showed a more efficient reduction in fibrosis and steatosis in the NASH model induced by an HFD than the groups receiving RES or SARO alone.

Neuroprotective potential of saroglitazar in 6-OHDA induced Parkinson's disease in rats.

Parkinson's disease (PD) is a neurodegenerative disorder that affects 2%-3% of the population worldwide. Clinical presentation of PD includes motor and non-motor symptoms. The interplay between pathogenic factors such as increased oxidative stress, neuroinflammation, mitochondrial dysfunction and apoptosis are responsible for neurodegeneration in PD. Intrastriatal administration of 6-hydroxy dopamine (6-OHDA) in rat brain provoked oxidative and nitrosative stress by decreasing endogenous antioxidants such as superoxide dismutase, catalase, glutathione, glutathione peroxidase and glutathione reductase. Consequently, interleukin-6, tumour necrosis-α, interferon-γ and cyclooxygenase-2 mediated neuroinflammation leads to mitochondrial dysfunction, involving inhibition of complex-II and IV activities, followed by apoptosis and degeneration of striatal dopaminergic neurons. Degeneration of dopaminergic neurons resulted in reduced dopamine turnover, consequently induced behavioural abnormalities in rats. Activation of peroxisome proliferator-activated receptors (PPARs) have protective role in PD by modulating response of antioxidant enzymes, neuroinflammation and apoptosis in various animal models of PD. Saroglitazar (SG) being dual PPAR-α/γ agonist activates both PPAR-α and PPAR-γ receptors and provide neuroprotection by reducing oxidative stress, neuroinflammation, mitochondrial dysfunction and apoptosis of dopaminergic cells in 6-OHDA induced PD in rats. Thereby, SG restored striatal histopathological damage and dopamine concentration in rat striatum, and behavioural alterations in rats. Thus, SG proved neuroprotective effects in rat model of PD. Potential benefits of SG in rat model of PD advocates to consider it for further preclinical and clinical evaluation.

Saroglitazar, a dual PPAR-α/γ agonist, alleviates LPS-induced hepatic and renal injury in rats.

Lipopolysaccharide (LPS), an endotoxin within gram-negative bacteria, is associated with systemic acute inflammatory response after invading living tissues and results in sepsis. The liver and kidney are both major target organs in sepsis. Septic acute hepatic-renal injury is a serious clinical condition with high risk of morbidity and mortality. Nevertheless, effective treatment is still lacking. This study highlights saroglitazar (SAR), a dual PPAR-α/γ agonist, as a proposed prophylactic drug against LPS-induced hepatic-renal injury. Rats were pretreated with SAR (2 and 4mg/kg/day) for 15days, while sepsis was induced by LPS injection (10mg/kg) on day 15 one hour following SAR oral administration. SAR pretreatment could successfully mitigate LPS-induced hepatic-renal injury, evidenced by enhancement of renal and hepatic functions and a decrease of tissue pathological injury. Meanwhile, SAR alleviated LPS-induced oxidative stress; it reduced malondialdehyde (MDA) levels and ameliorated decreased levels of superoxide dismutase (SOD) and glutathione (GSH). LPS-induced elevations in hepatic and renal nuclear factor-kappa B (NF-κB), phosphorylated inhibitor of kappa B alpha (p-IκBα), interferon-beta (IFN-β), and hepatic high mobility group box-1 (HMGB-1) contents were significantly attenuated in SAR-treated groups. SAR showed an advantageous impact against LPS-induced activation of non-canonical inflammasome and pyroptosis via a significant reduction in cysteinyl aspartate-specific proteinase-11 (Caspase-11) and gasdermin D (GSDMD) expressions. Moreover, Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptor Protein 3 (NLRP3) inflammasome activation with concomitant expression and activation of caspase-1 and release of interleukin-1beta (IL-1β) were considerably diminished following SAR pretreatment. SAR could be considered a prophylactic anti-inflammatory antioxidant drug against LPS-induced liver and kidney injury.

Effect of PPAR α/γ agonist on Behavioural Alterations in 6-OHDA induced Parkinson Disease

AIM- The aim of present research work aimed to investigate the neuroprotective potential of saroglitazor in experimental animal model of neurodegenerative disease. MATERIAL &amp; METHODS- Sixty Male Wistar albino rats (150-200 gm) were obtained from the Central Animal House of Pharmaceutical Sciences, India. The tablets of 4 mg Saroglitazar (SG), were weighed and finely powdered and then transferred into a 10-ml calibrated flask, dissolved in 4 ml sterile saline solution (0.9% NaCl), swirled and sonicated for 5 min, completed to volume with saline, and shaken well for 15 min immediately before administration. For the post operative care, Povidone-iodine was applied to all the animals for one week after surgery and gentamycin (7 mg/kg) were given to all animals 24 hourly for 2 days. The Rota rod unit consists of a rotating rod, 48 mm in diameter, which was divided into four parts by compartmentalization to permit the testing of four rats at a time. RESULTS- DC group showed marked (p &lt; 0.0001) decline in fall off time as compared to NC group. On the other hand, SG-1, SG-3 and SG-10 groups showed dose dependent remarkable (p&lt; 0.005, p&lt;0.0001, respectively) rise in fall off time when compared to DC group. SG-1, SG-3 and SG-10 groups showed drastic (p &lt; 0.0001) growth in forehand adjusting steps and noticeable (p &lt; 0.001) increment in backhand adjusting steps with exception of non significant rise with SG-1 group, when compared to DC group. CONCLUSION- In brief, for the first time we report that novel dual PPAR α/γ agonist, SG inhibited 6-OHDA-induced dopaminergic Neurodegeneration and mitigated behavioral alterations in rat model of PD.&#x0D; Keywords: Dopaminergic Neurodegeneration, Saroglitazar, Parkinson’s disease, Substantia nigra pars, Compacta region

Saroglitazar, a novel dual PPAR-α/γ agonist, reverses high fat-low protein diet-induced metabolic and cognitive aberrations in C57BL/6J male mice

AimsInsulin resistance (IR) has become one of the major causative factors for the pathogenesis of various metabolic and neurometabolic diseases. The sedentary lifestyle in association with the consumption of protein-deficient and high-calorie diet results in IR development. This study was aimed to evaluate the neuroprotective effects of Saroglitazar (SGZ), a dual peroxisome-proliferator activated receptor (PPAR-α/γ) in a high fat-low protein diet (HFLPD) fed mouse model of MetS and associated cognitive deficits. MethodsAdult male C57BL/6J mice were fed with HFLPD plus 15% oral fructose solution for 16 weeks. Starting at the 13th week, SGZ (5 & 10 mg/kg; p.o.) was administered along with HFLPD for four weeks, i.e., the 12th to 16th week of the study groups. Various physiological, serum metabolic, neurobehavioral, neuroinflammatory, and oxidative stress parameters were assessed. The brain histopathology and mRNA expression of diverse genes in specific brain regions were also estimated. ResultsThe treatment with SGZ at both doses have significantly reversed various HFLPD-induced metabolic and cognitive alterations by improving the glucose and lipid profile in the periphery in addition to the enhanced cerebral glucose homeostasis, BBB integrity, reduced oxidative stress, and neuroinflammation. Furthermore, the SGZ improved locomotion and memory retention while reducing the HFLPD-induced anxiety-like behaviors in the mice. ConclusionsSGZ treatment showed significant metabo-neuroprotective effects in mice fed with HFLPD, possibly through peripherally mediated activation of PPAR-α/γ and insulin downstream signaling in the cortex and hippocampus.

A Study to Evaluate the Effect of Saroglitazar in Type 2 Diabetes

A Study to Evaluate the Effect of Saroglitazar in Type 2 Diabetes

The dual PPAR-α/γ agonist saroglitazar ameliorates thioacetamide-induced liver fibrosis in rats through regulating leptin.

Liver fibrosis is a challenging global health problem resulting from chronic liver injury with no treatment currently available. It has been shown that activators for different peroxisome proliferator-activated receptor (PPAR) isoforms (α, γ, and δ) can affect different pathways in liver fibrosis. To evaluate the effects of the dual PPAR-α/γ agonist saroglitazar (SGZ) against thioacetamide (TAA)-induced fibrosis in rats, SGZ was administered for 6weeks together with TAA injection. Administration of SGZ ameliorated TAA-induced elevation in hepatic biomarkers. SGZ was able to inhibit periportal and intralobular fibrous connective tissue proliferation, to decrease hydroxyproline content, and to lower alpha smooth muscle actin (α-SMA) protein expression. To unearth the antifibrotic mechanism of SGZ, the role of several fibrotic markers was studied. SGZ possesses inhibitory effect on protein levels of leptin, transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB). Furthermore, SGZ rectified matrix degradation through decreasing tissue inhibitor of metalloproteinases-1 (TIMP-1). This study suggests that SGZ could have a possible antifibrotic effect via suppression of leptin that can repress TGF-β1 and PDFG-BB, with subsequent inhibition of TIMP-1.

Saroglitazar Deactivates the Hepatic LPS/TLR4 Signaling Pathway and Ameliorates Adipocyte Dysfunction in Rats with High-Fat Emulsion/LPS Model-Induced Non-alcoholic Steatohepatitis.

The most epidemic liver disorder non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with hepatocellular damage. Recently, it is predictable to be the extensive cause for liver transplantation. The absence of an approved therapeutic agent for NASH is the reason for investigating saroglitazar (SAR) which showed promising effects as a dual PPAR-α/γ agonist in recent studies on NASH. Here, we aimed to investigate the effect of SAR on NASH induced in rats by the administration of high-fat emulsion (HFE) and small doses of lipopolysaccharides (LPS) for 5weeks. Rats were divided into three groups: negative control group (saline and standard rodent chow), model group (HFE(10ml/kg/day, oral gavage) + LPS(0.5mg/kg/week, i.p)), and SAR-treated group (HFE(10ml/kg/day, oral gavage) + LPS(0.5mg/kg/week, i.p.) + SAR(4mg/kg/day, oral gavage) starting at week 3.Treatment with SAR successfully ameliorated the damaging effects of HFE with LPS, by counteracting body weight gain and biochemically by normalization of liver function parameters activity, glucose, insulin, homeostasis model of assessment (HOMA-IR) score, lipid profile levels, and histopathological examination. Significant changes in adipokine levels were perceived, resulting in a significant decline in serum leptin and tumor necrosis factor-α (TNF-α) level concurrent with adiponectin normalization. The positive effects observed for SAR on NASH are due to the downregulation of the LPS/TLR4 pathway, as indicated by the suppression of hepatic Toll-like receptor 4 (TLR4), NF-κB, TNF-α, and transforming growth factor-β1 (TGF-β1) expression. In conclusion, this work verified that SAR ameliorates NASH through deactivation of the hepatic LPS/TLR4 pathway and inhibition of adipocyte dysfunction.

Adverse drug reaction monitoring of newer oral anti-diabetic drugs - A pharmacovigilance perspective

Objective: To monitor and evaluate adverse drug reactions (ADRs) of newer oral anti-diabetic drugs in type II diabetics by spontaneous/solicited ADR monitoring. Material and methods: Two hundred and thirty two diabetic patients on newer oral antidiabetic drugs were evaluated prospectively in a cross-sectional study over a period of eighteen months. All patients were followed up for ADRs which were evaluated for incidence, frequency, severity and causality. ADR severity was graded according to University of Virginia Health System Adverse Drug Reaction Reporting program criteria and causality assessment was done using WHO-UMC scale. Results: 190 out of 232 patients (42 patients lost to follow up) were evaluated. ADRs were observed in 34 cases (17.9%). Most common ADRs were gastrointestinal (44.2%) followed by musculoskeletal (17.6%), metabolic (14.7%), infections (5.9%) and others (17.6%). The maximal frequency of ADRs was seen with sitagliptin (6.4%) followed by vildagliptin(3.8%), saxagliptin(2.7%), saroglitazar(2.1%), linagliptin(1.6%), canagliflozin(1.6%). 25(73.5%), 8(23.5%) and 1(3%) ADRs were mild, moderate and severe respectively. 24(70%) ADRs were classified as possible, 9(27%) probable and 1(3%) unlikely on causality assessment. Conclusion : Newer oral antidiabetic drugs like gliptins and SGLT-2 inhibitors have potential to cause ADRs. Gastro-intestinal, musculoskeletal, metabolic were most common ADRs. Active pharmacovigilance should be carried out for risk identification and management.