A Peripherally-Restricted Kappa Agonist (PRKA) as a Novel Approach to the Treatment of Menopausal Hot Flashes

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 515-547-Female Reproductive Endocrinology
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-541
Amy Elizabeth Oakley*1, Rakeb Million1, Lee Wohlen Organick1, Ryutaro Moriyama2, Katherine E Manbeck1, Jamie Rose Levin1, Susan D Reed1, Charles Chavkin1, Donald K Clifton1 and Robert A Steiner1
1University of Washington, Seattle, WA, 2Kinki Univ, Osaka, Japan
Millions of women transition through menopause every year and experience bothersome vasomotor symptoms (VMS) known as hot flashes/night sweats. Hot flashes are associated with sleep disturbances, mood disorders, heart palpitations, facial flushing, and a reduced quality of life. Hormonal therapies (HT) are effective treatments for hot flashes, but have life-threatening side effects. Nonhormonal therapies exist, but also have health risks and are less effective than HT. There is a compelling need to develop new, targeted, effective and safe treatments for hot flashes. Factors that trigger hot flashes are poorly understood, but it is clear that estrogen (E)-sensitive circuits in the brain mediate hot flashes, which are temporally correlated to activation of hypothalamic neural circuits governing pulsatile GnRH and LH secretion. Recent studies suggest that pulsatile GnRH secretion is itself governed by a network of E-sensitive neurons in the hypothalamic arcuate nucleus (ARC) that express kisspeptin, neurokinin B (NKB), and dynorphin (called KNDy neurons), as well as E receptor α. In humans, KNDy neurons are located in the infundibular nucleus in the hypothalamus, which is outside of the blood- brain barrier (and is homologous to the ARC in the rodent). KNDy neurons become super-activated following acute E withdrawal (e.g., with ovariectomy or menopause), and could in turn activate thermoregulatory circuits in the preoptic area (POA), sparking episodic VMS. If the network of KNDy neurons governing pulsatile GnRH secretion exerts a parallel activation of vasomotor pathways, it stands to reason that it would be possible to inhibit the E withdrawal-dependent instability of these vasomotor circuits by inhibiting the activity of KNDy neurons. Here we demonstrated that a selective, peripherally-restricted kappa agonist (PRKA), Tocris ICI 204,448 HCl (20 mg/kg, i.p.), in ovariectomized mice caused a profound decrease in plasma levels of LH 10 min after drug injection (compared to vehicle-treated control). The PRKA had no effect on body temperature or behavior. Thus, a PRKA-mediated blockade of kappa signaling in women could, in theory, ameliorate the VMS of hot flashes— and avoid the adverse effects of a centrally active KA (e.g., dysphoria), as well as the cardiovascular and cancer risks of HT.

Nothing to Disclose: AEO, RM, LWO, RM, KEM, JRL, SDR, CC, DKC, RAS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm