PARP (IC50 =120 μM)

BGP-15 (15 mg/kg, p.o.) does not ameliorate skeletal muscle pathology in older mdx mice. While BGP-15 does not stop diaphragm atrophy, it does significantly (roughly 100%) improve diaphragm muscle fiber function in a rat model. Enhancement of mitochondrial content and function is also achieved by the treatment's protection against myosin PTMs linked to PARP-1 inhibition and HSP72 induction. In Ntg mice or a separate cohort of adult, normal wild-type mice, BGP-15 (15 mg/kg per day in saline) treatment has no effect on morphology, cardiac function, or ECG parameters. The increase in lung weight and atrial size is lessened by BGP-15 treatment. Treatment with BGP-15 can stop or lessen arrhythmia episodes. Treatment with BGP-15 can stop or lessen arrhythmia episodes. In the HF+AF model, a shorter PR interval is linked to BGP-15 treatment.

The protective effect of O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) against ischemia-reperfusion-induced injury was studied in the Langendorff heart perfusion system. To understand the molecular mechanism of the cardioprotection, the effect of BGP-15 on ischemic-reperfusion-induced reactive oxygen species (ROS) formation, lipid peroxidation single-strand DNA break formation, NAD(+) catabolism, and endogenous ADP-ribosylation reactions were investigated. These studies showed that BGP-15 significantly decreased leakage of lactate dehydrogenase, creatine kinase, and aspartate aminotransferase in reperfused hearts, and reduced the rate of NAD(+) catabolism. In addition, BGP-15 dramatically decreased the ischemia-reperfusion-induced self-ADP-ribosylation of nuclear poly(ADP-ribose) polymerase(PARP) and the mono-ADP-ribosylation of an endoplasmic reticulum chaperone GRP78. These data raise the possibility that BGP-15 may have a direct inhibitory effect on PARP. This hypothesis was tested on isolated enzyme, and kinetic analysis showed a mixed-type (noncompetitive) inhibition with a K(i) = 57 +/- 6 microM. Furthermore, BGP-15 decreased levels of ROS, lipid peroxidation, and single-strand DNA breaks in reperfused hearts. These data suggest that PARP may be an important molecular target of BGP-15 and that BGP-15 decreases ROS levels and cell injury during ischemia-reperfusion in the heart by inhibiting PARP activity [4].

According to a previous study, BGP-15 at 200 μM could prevent oxidative damages caused by imatinib, reduce the loss of high-energy phosphates, change the way imatinib signals by preventing the activation of JNK and p38 MAP kinase, as well as phosphorylate GSK-3β and Akt.

Male adult HF+AF and Ntg mice, who are approximately 4 months old, are given BGP-15 (15 mg/kg daily in saline) or left untreated (oral gavage with saline or no gavage) for 4 weeks. In the HF+AF model, gavage with saline has no effect on morphological or functional parameters. Thus, mice receiving saline injection and mice left untreated (no gavage) are grouped together and referred to as HF+AF control. ECG and echocardiography scans are carried out both before and after therapy.

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\n\nExperimental protocols[3]
\nProtocol 1: Adult (~4 month) male HF+AF and Ntg mice were administered with BGP-15 (15 mg kg−1 per day in saline, N-Gene Research Laboratories) for 4 weeks by oral gavage or remained untreated (oral gavage with saline or no gavage). Gavage with saline had no effect on morphological or functional parameters in the HF+AF model (Supplementary Fig. 3). Therefore, untreated mice (no gavage) and mice administered saline are combined and referred to as HF+AF control. Echocardiography and ECG studies were performed before and after treatment.[3]
\n\nProtocol 2: To determine whether BGP-15 provided protection via HSP70, BGP-15 (15 mg kg−1 per day, oral gavage) was administered to adult (~14 weeks) male and female HF+AF mice deficient for HSP70 (HF+AF-HSP70 KO) for 4 weeks.[3]
\n\nProtocol 3: To assess whether an increase in HSP70 could mediate protection in the HF+AF model, male HF+AF mice overexpressing HSP70 (HF+AF-HSP70 Tg) were generated and characterized at ~12–13 weeks.[3]
\n\nProtocol 4: To examine whether overexpression of IGF1R in the heart could provide protection in the HF+AF model, male HF+AF mice overexpressing IGF1R (HF+AF-IGF1R Tg) were generated and characterized at ~16–17 weeks.[3]
\n\nProtocol 5: To determine whether IGF1R could mediate protection in the HF+AF model independent of HSP70, male and female HF+AF-IGF1R Tg-HSP70 KO mice were generated and characterized at ~11 weeks.[3]
\n \nProtocol 6: To examine whether BGP-15 had the capacity to provide protection in an additional model with HF and AF, 11- to 12-month-old male MURC Tg were administered with BGP-15 (15 mg kg−1 per day, oral gavage) or saline for 4 weeks.[3]

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\n\nTo assess whether BGP-15 administration could confer effects on an already established dystrophic pathology, 20-week-old mdx and 8-week-old dko mice were administered BGP-15 (15 mg/kg in 0.9% sterile saline; N-Gene Research Laboratories Inc., New York, NY) daily via oral gavage for 4 (dko) or 5 (mdx) weeks. Age-matched vehicle-treated dystrophic and healthy wild-type control (C57BL/10) mice received an equivalent volume of 0.9% sterile saline via daily oral gavage. Because of the severity of the dko phenotype, a shorter treatment period was used with a significant number of mice reaching humane end point criteria (ie, kyphosis score of 5 and sustained 15% loss of body mass) after 12 weeks of age. The average lifespan of mice in our dko colony was approximately 14 to 15 weeks, with the severity of the dystrophic pathology at 8 weeks of age (when treatment commenced) indicated by an average kyphosis score of 2.5. The kyphosis score indicates the severity of spinal curvature on palpation of conscious mice and ranked 1 to 5, with 1 indicating no spinal deformity and 5 being the most severe. To assess the effect of BGP-15 administration as a preventive treatment for the dystrophic cardiomyopathy and to confirm previous findings on skeletal muscles of young mice,14 4-week-old dko mice were administered BGP-15 (15 mg/kg in 0.9% sterile saline daily via oral gavage) for 5 to 6 weeks, with other groups of aged-matched dko and C57BL/10 mice treated similarly with vehicle only. Because BGP-15 is a hydroxylamine derivative that affects only stressed cells, a group of C57BL/10 mice treated with BGP-15 was not included.10,14,34 Previous studies investigating BGP-15 effects on skeletal muscle and heart observed no morphological or functional changes in either tissue, in wild-type mice after long-term treatment.14,34 To assess Hsp72 induction via BGP-15, 4- and 10-week-old dko mice and age-matched C57BL/10 mice were administered a single bolus of BGP-15 (15 mg/kg) via oral gavage, and the tibialis anterior (TA) muscles, heart, and diaphragm were excised 6 hours later, frozen in liquid nitrogen, and stored at −80°C for later analyses.[1]

[1]. BGP-15 Improves Aspects of the Dystrophic Pathology in mdx and dko Mice with Differing Efficacies in Heart and Skeletal Muscle. Am J Pathol. 2016 Dec;186(12):3246-3260.

[2]. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction. Sci Transl Med. 2016 Aug 3;8(350):350ra10.

[3]. The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nat Commun. 2014 Dec 9;5:5705.

[4]. Improvement of insulin sensitivity by a novel drug candidate, BGP-15, in different animal studies. Metab Syndr Relat Disord. 2014 Mar;12(2):125-31.

[5]. BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases. Mol Cell Biochem. 2012 Jun;365(1-2):129-37.

[6]. BGP-15, a nicotinic amidoxime derivate protecting heart from ischemia reperfusion injury through modulation of poly(ADP-ribose) polymerase. Biochem Pharmacol. 2000 Apr 15;59(8):937-45.

Duchenne muscular dystrophy is a severe, progressive rhabdomyotrophic disorder that leads to respiratory and/or heart failure, ultimately resulting in premature death. We previously demonstrated that treatment with the heat shock protein 72 co-inducer BGP-15 in young malnourished MDX mice and dystrophin/myotrophic knockout (dko) mice improved their malnutrition pathology. Therefore, we hypothesized that late-stage BGP-15 treatment in older MDX and DKO mice would be equally effective given established malnutrition pathology. However, late-stage BGP-15 treatment in either MDX or DKO mice did not improve the maximum contractile force of the tibialis anterior (TA) (in vivo) or the diaphragmatic strip (in vitro). However, collagen deposition (fibrosis) was reduced in the tibialis anterior (TA) of BGP-15-treated DKO mice, but not in the TA of treated MDX mice or the diaphragm of treated MDX and DKO mice. We also investigated whether BGP-15 treatment could improve certain aspects of cardiac pathology, and the results showed that in young dko mice, BGP-15 treatment reduced collagen deposition and improved cell membrane integrity and contractile function. These results confirm that BGP-15 can improve certain aspects of malnutrition pathology, but its efficacy on the heart and skeletal muscle varies at different stages of disease progression. These findings support the role of BGP-15 in a range of pharmacological treatments for Duchenne muscular dystrophy and related diseases. [1]

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Ventilation-induced diaphragmatic dysfunction (VIDD) refers to a significant decline in diaphragmatic function after mechanical ventilation, which has a negative impact on patients’ quality of life and the healthcare system, but there is currently a lack of targeted treatment strategies. We used an experimental intensive care unit (ICU) model to conduct time-resolved studies on changes in diaphragmatic structure and function caused by long-term mechanical ventilation and the effects of pharmacological intervention (the molecular chaperone co-inducer BGP-15). The significant loss of diaphragmatic fiber function caused by mechanical ventilation is caused by post-translational modification (PTM) of myosin. In rat models, diaphragmatic fiber function was significantly improved (approximately 100%) after 10 days of BGP-15 treatment, but diaphragmatic atrophy was not reversed. The treatment also protected the diaphragm from the effects of myosin PTM associated with HSP72 induction and PARP-1 inhibition, thereby improving mitochondrial function and content. Therefore, BGP-15 may provide an intervention strategy for reducing ventilator-associated diaphragmatic dysfunction (VIDD) in mechanically ventilated ICU patients. [2] Heart failure (HF) and atrial fibrillation (AF) share common risk factors, often occur together, and have high mortality rates. Treatment of heart failure (HF) with atrial fibrillation remains a major unsolved problem. This study showed that the small molecule BGP-15 improved cardiac function and reduced the occurrence of arrhythmias in two independent mouse models that gradually developed heart failure and atrial fibrillation. In these models, BGP-15 treatment was associated with increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R), while phosphorylation of IGF1R was significantly reduced in atrial tissue samples from patients with atrial fibrillation. Overexpression of the heart-specific IGF1R transgene in mice with heart failure and atrial fibrillation reproduced the protective effect observed with BGP-15. We further confirmed that BGP-15 and IGF1R provide protection independent of phosphatidylinositol 3-kinase-Akt and heat shock protein 70, which are often deficient in aging and diseased hearts. Given that BGP-15 is safe and well-tolerated in humans, this study reveals a potential approach for treating heart failure and atrial fibrillation. [3]

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Background: Insulin resistance has been considered the most important predictor of the further development of type 2 diabetes mellitus (T2DM). This study investigated the effect of the heat shock protein (HSP) co-inducer BGP-15 on insulin sensitivity in different insulin-resistant animal models and compared it with insulin secretagogues and insulin sensitizers. Methods: Insulin sensitivity in normal rabbits, high-cholesterol-fed rabbits, and healthy Wistar and Goto-Kakizaki (GK) rats was assessed using the high-insulin positive glucose clamp technique, and dose range studies were conducted. We also investigated the effect of BGP-15 on streptozotocin-induced aortic vasodilation in Sprague-Dawley rats. Results: In cholesterol-fed rabbits, BGP-15 at doses of 10 mg/kg and 30 mg/kg increased insulin sensitivity by 50% and 70%, respectively, but this was not observed in normal rabbits. In GK rats with hereditary insulin resistance, glucose infusion rate increased in a dose-dependent manner after 5 days of BGP-15 treatment. The most effective dose was 20 mg/kg, which increased insulin sensitivity by 71% compared to the control group. Administration of BGP-15 protected blood vessels from streptozotocin-induced changes, with effects similar to rosiglitazone. Conclusion: Our results indicate that the insulin-sensitizing effect of BGP-15 is comparable to that of conventional insulin sensitizers. This may have clinical value for the treatment of type 2 diabetes. [4]

C14H24CL2N4O2

351.27

278.174

C, 60.41; H, 7.97; N, 20.13; O, 11.50

66611-38-9

9817104

Light yellow to yellow solid powder

1.203

2

5

6

20

306

0

OC(CN1CCCCC1)CONC(C1=CC=CN=C1)=N

MVLOQULXIYSERZ-UHFFFAOYSA-N

InChI=1S/C14H22N4O2/c15-14(12-5-4-6-16-9-12)17-20-11-13(19)10-18-7-2-1-3-8-18/h4-6,9,13,19H,1-3,7-8,10-11H2,(H2,15,17)

N'-(2-hydroxy-3-piperidin-1-ylpropoxy)pyridine-3-carboximidamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)