ICI 63197

Tamoxifen and ICI 182,780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats.[Pubmed:28063803]

Horm Behav. 2017 Mar;89:98-103.

In the female rat, sexual receptivity (lordosis) can be facilitated by sequential activation of estrogen receptor (ER) alpha and G protein-coupled estrogen receptor 1 (GPER) by estradiol. In the estradiol benzoate (EB) primed ovariectomized (OVX) rat, EB initially binds to ERalpha in the plasma membrane that complexes with and transactivates metabotropic glutamate receptor 1a to activate beta-endorphin neurons in the arcuate nucleus of the hypothalamus (ARH) that project to the medial preoptic nucleus (MPN). This activates MPN mu-opioid receptors (MOP), inhibiting lordosis. Infusion of non-esterified 17beta-estradiol into the ARH rapidly reduces MPN MOP activation and facilitates lordosis via GPER. Tamoxifen (TAM) and ICI 182,780 (ICI) are selective estrogen receptor modulators that activate GPER. Therefore, we tested the hypothesis that TAM and ICI rapidly facilitate lordosis via activation of GPER in the ARH. Our first experiment demonstrated that injection of TAM intraperitoneal, or ICI into the lateral ventricle, deactivated MPN MOP and facilitated lordosis in EB-primed rats. We then tested whether TAM and ICI were acting rapidly through a GPER dependent pathway in the ARH. In EB-primed rats, ARH infusion of either TAM or ICI facilitated lordosis and reduced MPN MOP activation within 30min compared to controls. These effects were blocked by pretreatment with the GPER antagonist, G15. Our findings demonstrate that TAM and ICI deactivate MPN MOP and facilitate lordosis in a GPER dependent manner. Thus, TAM and ICI may activate GPER in the CNS to produce estrogenic actions in neural circuits that modulate physiology and behavior.

ICI-RS 2015-Is a better understanding of sleep the key in managing nocturia?[Pubmed:27653805]

Neurourol Urodyn. 2018 Sep;37(7):2048-2052.

AIMS: Nocturia, or waking up at night to void, is a highly prevalent and bothersome lower urinary tract symptom. However, the applied treatment modalities do not improve symptoms in about half of the patients. The aim of this report is to generate new ideas for future nocturia research, with special emphasis on the role of sleep physiology and sleep disorders. METHODS: The following is a report of the presentations and subsequent discussion of the Nocturia Think Tank session at the annual meeting of the International Consultation on Incontinence Research Society (ICI-RS), which took place in September 2015 in Bristol. General information about the organization of the ICI-RS meeting can be found on the website "www.ici-rs.org." An overview of challenges within the existing evidence, future research ideas, and results of research with regard to nocturia and sleep were presented. RESULTS AND CONCLUSION: In order to optimize the management of nocturia and nocturnal polyuria (NP), future research has to focus on the development of unambiguous terminology regarding nocturia and NP, the role of renal function profiles and simplified frequency volume charts as guidance of individualized therapy and the role of sleep disorders such as periodic limb movements during sleep and habitual voiding as a response to awakening. Neurourol. Urodynam. 37:2048-2052, 2018. (c) 2016 Wiley Periodicals, Inc.

Inhibitor binding to type 4 phosphodiesterase (PDE4) assessed using [3H]piclamilast and [3H]rolipram.[Pubmed:12704225]

J Pharmacol Exp Ther. 2003 May;305(2):565-72.

Piclamilast is a type 4 phosphodiesterase (PDE4) inhibitor with equal affinity for the high-affinity rolipram binding site (HARBS) and low-affinity rolipram binding site (LARBS). The binding of [(3)H]piclamilast to preparations of rat brain and peripheral tissue was investigated and compared with that of [(3)H]rolipram. [(3)H]piclamilast binding was high-affinity, saturable, reversible, and partially Mg(2+)-dependent. Binding was detected both to membrane and soluble fractions, with K(d) values of 3.1 and 4.5 nM, respectively. The B(max) values for [(3)H]piclamilast were about 1.5-fold greater than that of [(3)H]rolipram binding, suggesting that [(3)H]piclamilast, but not [(3)H]rolipram, binds to LARBS as well as the HARBS. The HARBS was present in all the brain regions examined, but not in peripheral tissues. All PDE4 inhibitors tested were potent competitors for [(3)H]piclamilast binding; the competition curves for rolipram, desmethylpiclamilast, ICI 63,197, and Ro 20-1724 were better described by a two-site model, while the competition curves for piclamilast, cilomilast, roflumilast, and CDP 840 were adequately described by a one-site model. Inhibitors of other PDE families were much less potent. The inhibition of [(3)H]piclamilast was further tested in the presence of 1 microM rolipram to isolate the LARBS. Under this condition, the competition curves for all the inhibitors were adequately described by a one-site model, with K(i) values close to that for the LARBS. The results indicated that [(3)H]piclamilast is a useful tool to directly study inhibitor interaction with the HARBS and the LARBS in rat brain.

Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors.[Pubmed:6302550]

Neuropharmacology. 1983 Mar;22(3):267-72.

Following intraperitoneal administration, the selective cAMP phosphodiesterase (PDE) inhibitors rolipram, ICI 63 197 and Ro 20-1724 were investigated in mice in comparison with imipramine for their effectiveness in two classical test models for prediction of clinical antidepressant activity: antagonism of reserpine-induced hypothermia or hypokinesia and potentiation of yohimbine lethality. Rolipram was approximately 15 times more potent than imipramine or Ro 20-1724 and approximately as potent as ICI 63 197 in antagonizing reserpine-induced hypothermia. The antihypothermic effect of the phosphodiesterase inhibitors occurred at a smaller dose than that of imipramine. In contrast to imipramine, the phosphodiesterase inhibitors reversed reserpine-induced hypokinesia. Rolipram was approximately as potent as ICI 63 197 and about 15 times more potent than Ro 20-1724. Rolipram was approx. 5 times more potent than Ro 20-1724 and approx. as potent as imipramine or ICI 63 197 in potentiating the lethality of yohimbine. In both test models the (-)-isomer of rolipram was approx. 10-15 times more potent than the (+)-isomer, indicating a stereospecific mechanism of action. The present data suggest an antidepressant action of selective cAMP phosphodiesterase inhibitors due to enhancement of central noradrenergic transmission. The hypothesis is put forward that the increase of noradrenaline turnover induced by phosphodiesterase inhibitors in conjunction with the inhibitory action of the compounds on cAMP metabolism enables more efficient adaptative changes to occur at central synapses resulting in a rapid onset of the antidepressant activity. Preliminary results with rolipram in patients with endogenous depression seem to support this assumption.