Effects of prenatal PPAR-γ agonist rosiglitazone exposure on rat hippocampus development in a time-dependent manner: A stereological and histopathological study

Abstract

Rosiglitazone is in the thiazolidinedione class of drugs used in the treatment of type 2 diabetes mellitus. It works as an insulin sensitizer by binding to the peroxisome proliferator-activated receptor gamma. We investigated the effects of prenatally administered rosiglitazone on pyramidal cell numbers and morphologies in the hippocampus at postnatal period using histochemical and stereological techniques, congenital morphological properties and the number of offspring in rats. Eighteen female rats were grouped into control (C), low-dose rosiglitazone (LDR) and high-dose rosiglitazone (HDR). LDR pregnant rats received 2 mg/kg/day of rosiglitazone via oral gavage during the first 16 days of the pregnancy. HDR rats received 5 mg/kg/day. The infants were grouped into newborn (NB), 4 week (4 W) and 12 week (12 W). A side from histopathologic and congenital assessments, stereological analyses were performed using the optical fractionator method. Congenital anomaly was not detected in any of the rosiglitazone treatment groups, and their number of offspring was similar to that of the C group. Stereological counts revealed a significant reduction in the number of hippocampal pyramidal cells in the C and LDR groups but not in the HDR group until birth to 12th week. When NB groups were compared, the number of pyramidal cells in the HDRNB group was less than those in the LDRNB and CNB groups. HDR affected apoptosis or the proliferation and maturation of progenitor cells to the pyramidal neuron during neurodevelopment in the hippocampus, whereas LDR did not adversely affect neuronal development and did not cause congenital anomalies.

Clinical Evidence of Antidepressant Effects of Insulin and Anti-Hyperglycemic Agents and Implications for the Pathophysiology of Depression—A Literature Review

“…Adverse effects of PPARγ receptor agonists on neuronal function were also noted in both animal and human studies [65]. Rosiglitazone was associated with neuronal apoptosis in the hippocampus of rats [66], and cognitive complications in patients with T2DM [67]. Although the use of PPARγ receptor agonists in T2DM is declining due to its adverse effects, a meta-analysis suggested a relatively favorable safety in MDD patients [32].…”

Understanding PPARγ and Its Agonists on Trophoblast Differentiation and Invasion: Potential Therapeutic Targets for Gestational Diabetes Mellitus and Preeclampsia

“…However, due to the inability of rosiglitazone to cross the placenta during early gestation [104] but potential transfer and metabolism by embryos during late gestation [105,106], studies have been conducted to assess its safety during pregnancy. Although limited data support its safety, several studies have shown that low doses of rosiglitazone do not have adverse effects on fetal development [107][108][109][110]. However, some studies have demonstrated that activation of PPARγ by rosiglitazone disrupts the vascularity and morphology of murine placenta [111,112].…”