Circulating Levels of Allopregnanolone, a Neuroactive Steroid, and Leptin during Treatment with Valproic Acid in Children with Epilepsy

Abstract

Weight gain is a well-known unwanted effect of valproic acid (VPA) therapy. Studies on VPA-associated changes of homeostatic hormones remain limited and controversial. Allopregnanolone (AP) is a circulating neuroactive steroid involved in modulation of behavioral activities whose serum levels are increased in obese children. The aim of the present study was to determine whether VPA therapy affects leptin and AP circulating levels in prepubertal girls with epilepsy. One-hundred and one patients were divided into four groups: epileptic patients with VPA-associated obesity (n = 21); lean epileptic patients under VPA therapy (n = 35); healthy obese children (n = 23), and healthy lean children (n = 22). Patients with VPA-associated obesity had significantly enhanced blood concentrations of AP (p = 0.001) and leptin (p = 0.007) than lean subjects. There were no differences in leptin and AP plasma levels between patients with VPA-associated obesity and obese controls (p = 0.45 and p = 0.10, respectively), as there were no differences between lean patients under VPA therapy and lean healthy controls (p = 0.06). In patients under VPA therapy, both plasma leptin and AP levels were significantly correlated with BMI (r = 0.074, p = 0.02, and r = 0.084, p = 0.01, respectively). Plasma leptin concentrations were not correlated with AP levels (r = 0.023, p = 0.13). In conclusion, a correlation between obesity and neuroactive steroids was shown. It remains to be established whether the increased circulating level of AP is a secondary effect of anxiolytic-sedative processes occurring in subjects with obesity-related emotional and behavioral anomalies, or plays a central role in determining abnormal eating behaviors.

Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders

“…In humans, serum levels of ALLO are normally stable during the first 2 years of life (212). Obese children have been reported to have elevated circulating levels of ALLO, but how this influences their learning and memory function later in life has not been elucidated (213). In post-menopausal women, the effects of ALLO on mood appears to be dose dependent and to follow an inverted U-shaped cure (214).…”

GABAA receptor currents in the dorsal motor nucleus of the vagus in females: influence of ovarian cycle and 5α-reductase inhibition

“…However, increased 5␣-reductase activity has been implicated in the glucose intolerance associated with polycystic ovarian syndrome. Allopregnanolone has been linked to weight gain in rodents ( Holmberg et al 2014Holmberg et al , 2015 and humans (Grosso et al 2011;Menozzi et al 2002;Predieri et al 2007). However, allopregnanolone has also been shown to prevent glucose-mediated cellular apoptosis and attenuate thermal hyperalgesia (markers of diabetic neuropathy in rats) (Afrazi et al 2014).…”