Oestrogen receptor agonists ERα and ERβ ameliorate oxidative brain injury and improve memory dysfunction in rats with an epileptic seizure.

• What is the central question of this study? Could different hormonally active substances, including oestrogen receptor (ER) agonists, protect against oxidative brain damage and memory impairment induced by a single epileptic seizure in rats? If so, which signalling mechanisms are involved in their anti-inflammatory effects? • What is the main finding and its importance? Chronic administration of oestrogen, progesterone, ER modulators/agonists or blockade of testosterone exhibited anti-inflammatory and antioxidant actions on single seizure-induced neuronal injury, while ER agonists additionally improved memory function and up-regulated CREB signalling and hippocampal GABA(A)α1 receptor density, suggesting that ERα or ERβ receptor activation may be beneficial in protecting against seizure-related oxidative brain injury and cognitive dysfunction.

The susceptibility to epileptic seizures is dependent on sex as well as fluctuations in oestrogen levels, while exogenous oestrogen was shown to have no effect or facilitate or inhibit seizure activity. Oestrogen receptors (ER) mediate antioxidant and antiinflammatory actions in several inflammatory models, but the involvement of oestrogen receptors on seizure-induced neuronal injury was not evaluated before. In order to assess the effects of resveratrol, progesterone, oestradiol (E2), an anti-testosterone (CPA), a selective ER modulator (TMX), and ERα/ERβ agonists (PPT/DPN) on oxidative brain damage and memory impairment due to epileptic seizure, male Wistar rats (n = 120) received one of the treatment choices either in drinking water or intraperitoneally for 31 days, and epileptic seizure was induced on the 28^th day by a single-dose pentylenetetrazole (PTZ; 45 mg k^-1 g) injection. The results demonstrate that chronic pretreatments with resveratrol, progesterone, E2, CPA or TMX suppressed most of the inflammatory parameters indicative of oxidative neuronal injury, while treatments with ER agonists DPN or PPT were found to be even more effective in limiting the oxidative damage. Treatment with DPN resulted in the up-regulation of CREB and BDNF expressions, while PPT up-regulated expression of CREB without affecting BDNF levels. Moreover, both ER agonists provided a protection against seizure-induced memory loss with a concomitant increase in hippocampal GABA(A)α1-positive cells. In conclusion, ER agonists and more specifically ERβ agonist appears to provide maximum protection against seizure-induced oxidative brain injury and associated memory dysfunction by up-regulating the expressions of CREB, BDNF and GABA(A)α1 receptors. This article is protected by copyright. All rights reserved.