Lídia M Lima, Margarete M Trachez, Josenildo Segundo Chaves de Araujo, Jaqueline Soares da Silva, Daniel Nascimento do Amaral, Roberto T Sudo, Eliezer J Barreiro and Gisele Zapata-Sudo
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.