Novel Partial Agonist of PPAR-Gamma for Treatment of Diabetic Neuropathy in Rats

Abstract

This work describes a novel ligand for peroxisome proliferator-activated receptor gamma (PPARgamma) and its hypoglycemic and analgesic activity in a murine model of diabetes-induced neuropathic pain. The molecular recognition of LASSBio-1772 by a PPARgamma binding domain showed that the compound is a partial agonist. Four weeks after male Wistar rats received a single intravenous injection of streptozotocin (STZ, 60 mg/kg), plasma glucose levels were increased from 92.5 ± 3.7 to 465.0 ± 21.6 mg/dL (P < 0.01) and serum insulin was reduced from 66.8 ± 7.8 to 25.5 ± 5.6 pmol/L (P<0.01). Diabetic animals were then, treated with either vehicle or LASSBio-1772 (50 mg/kg, i.p.) daily for 7 days. LASSBio-1772 significantly reduced blood glucose levels to 242.0 ± 55.1 mg/dL (P<0.05) and increased insulin levels to 58.7 ± 14.8 pmol/L (P<0.05), indicating the hypoglycemic activity of this compound. LASSBio-1772 also reduced the elevated triglyceride levels induced by STZ treatment from 74.1 ± 8.6 to 34.0 ± 6.3 mg/dL (P<0.01). LASSBio-1772 could reduce serum glucose levels via increased insulin levels and potentially improve insulin sensitivity. Neuropathy was detected after four weeks of STZ-induced diabetes, with reduced thermal heat withdrawal latency from 11.7 ± 0.1 to 7.1 ± 0.2 s (P<0.01) and paw withdrawal threshold from 37.5 ± 2.1 to 29.9 ± 1.1 g (P<0.05) indicating the establishment of hyperalgesia and allodynia. LASSBio-1772 treatment restored both measures to non-diabetic values (12.2 ± 0.4 s and 34.5 ± 1.5 g). In conclusion, treatment with LASSBio-1772, a partial PPARgamma agonist, decreased hyperglycemia and neuropathic pain induced by diabetes. PPARgamma stimulation by LASSBio-1772 could prevent inflammation and inhibit both peripheral and central sensitization.

Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents

“…Compound 9 (LASSBio-1772) did not reduce hyperglycemia after treatment with a single dose ( Figure 6 ), although it was recently described by Lima et al as a partial agonist of PPARγ. 14 When administered for 7 days at a dose of 50 mg/kg, it produced a significant reduction in glucose levels (242.4±55.3 mg/dL) when compared to vehicle (410.0±58.0 mg/dL).…”

“…Sulfonylhydrazones 4, 7, and 8 were prepared in two linear steps based on hydrazinolysis of starting material 11 followed by condensation with functionalized aldehydes to produce good yields of the target compounds. 14 N-methyl-sulfonylhydrazone analogs (5, 6, and 9) were synthetized in a similar manner using N-methyl-sulfonylhydrazide 13 as a key intermediate. This compound was obtained with 39.5% overall yield through protection from phthalic anhydride, followed by N-methylation with methyl iodide and deprotection of phthalimide, using hydrazine hydrate in ethanol ( Figure 2 ).…”

“…The anti-diabetic profile of compounds 4–9 was investigated through the evaluation of their ability to reduce blood glucose levels in a murine model of diabetes induced by STZ. 13 , 14 Among these compounds, only sulfonylhydrazones 6 and 7 showed hypoglycemic activity. After ip administration of a single dose, LASSBio-1773 (20 mg·kg −1 ) (7) significantly reduced blood glucose from 384.0±41.9 mg/dL to 182.2±22.7 mg/dL and LASSBio-1774 (6) reduced it from 397.1±38.2 mg/dL to 255.3±42.2 mg/dL ( Figure 6 ).…”

“…Considering the fact that the sulfonylhydrazone 9 (LASSBio-1772), which has high chemical and plasma stability ( Tables 1 and 2 ), had been described as an antinociceptive agent in a diabetic neuropathic pain model induced by STZ in rats, 14 analog 7 (LASSBio-1773) was selected to be evaluated on the same experimental model. As shown in Figure 7 , long-term administration of compound 7 (dose 50 mg·kg −1 , ip) reduced diabetic neuropathic pain.…”

“…In order to investigate the mechanism of the action of compounds 4–9 and considering that these compounds were designed based on molecular modification of the prototype LASSBio-1471 (3), previously described as PPARγ ligand, 14 PPARγ binding assay was performed by CEREP ® , employing a single concentration of compounds 4–9 (C =30 µM) using rosiglitazone as positive control. In this model, these compounds were not able to inhibit the control specific binding to PPARγ.…”