Disease relevance of AY-9944

• In in vitro experiments using microsomes from livers of control bile fistula rats, the addition of AY9944 (up to 100 microM) failed to inhibit cholesterol 7 alpha-hydroxylase activity [1].
• The AY9944 model of chronic atypical absence seizures in rats reliably reproduces the electrographic, behavioral, pharmacological and cognitive features of clinical atypical absence [2].
• The malformations could have been caused by the same mechanism as holoprosencephaly after early treatment with AY9944 [3].
• Inhibition of 7-dehydrocholesterol reductase by the teratogen AY9944: a rat model for Smith-Lemli-Opitz syndrome [4].

Psychiatry related information on AY-9944

• Therefore, we examined the effect of a specific, high affinity GABA(B) receptor antagonist, CGP35348, on the atypical absence seizures, the working memory deficits, and the altered long-term potentiation that we have observed in the AY9944 model [2].

High impact information on AY-9944

• A time course study that examined the effects of the female estrous cycle on the chronic slow spike-and-wave discharges (SSWDs), gamma-aminobutyric B receptor (GABA(B)R) binding, and GABA(B)R protein expression was conducted in Long Evans hooded rats treated during development with a cholesterol synthesis inhibitor AY9944 (AY) [5].
• The data indicate that there is a significant increase in both the duration of SSWD and GABA(B)R binding in the AY model, during the proestrus stage of the estrous cycle, the stage during which the levels of progesterone are at their highest [5].
• The effects of different concentrations of the hypocholesterolemic drug AY9944, an inhibitor of delta7-reductase, on organotypic cultures of fetal mouse spinal cord, were studied by light and electron microscopy [6].
• Both, hypoosmotic ROS generation and p47(phox) serine phosphorylation were sensitive to the acidic sphingomyelinase inhibitors AY9944 and desipramine, the protein kinase C (PKC)zeta-inhibitory pseudosubstrate peptide, the NMDA receptor antagonist MK-801 and the intracellular Ca(2+) chelator BAPTA-AM [7].
• The method relies on the ability of AY9944, a potent and relatively selective inhibitor of cholesterol synthesis, to cause the time-dependent accumulation of 7-dehydrocholesterol (DHC), a cholesterol precursor detected with sensitivity and specificity by reverse-phase HPLC-coupled spectrophotometry at 282 nm [8].

Chemical compound and disease context of AY-9944

• Our aim is to verify the validity of a rat model proposed for Smith-Lemli-Opitz (SLO) syndrome, a developmental disorder characterized by a defect in 7-dehydrocholesterol-delta 7 (7DHC)-reductase and by facial dysmorphism close to the holoprosencephaly caused by the teratogen AY9944 [4].

Biological context of AY-9944

• CGP35348 blocked atypical absence seizures, restored long-term potentiation to normal level, and reversed the cognitive deficit in the AY9944-treated animals [2].
• Histology of retinas from unexposed, AY9944-treated rats (6-week-old) was normal [9].
• AY9944 was given orally to rats on gestation day 3 (D3) [4].

Anatomical context of AY-9944

• Combined effects of AY9944 and plasma LDL (or whole plasma) on lymphocyte blastic transformation [10].
• AY9944 treatment for 4 to 7 days retarded cultures revealed anaccumulation of numerous intracytoplasmic inclusions in perikarya of neurons, astrocytes,and oligodendrocytes [11].
• Effect of hypocholesterolemic agents on central nervous system cholesterol biosynthesis III. Zuclomiphene in combination with AY9944 and triparanol [12].
• Production of the two bile salts was inhibited by 70-80% in hepatocytes from AY9944-treated as compared to untreated animals [13].

Associations of AY-9944 with other chemical compounds

• Inhibition of sterol and DNA synthesis in peripheral blood lymphocytes by AY9944 [14].

Gene context of AY-9944

• At the early-somite stage we observed a reduction of Shh signaling in AY9944 treated embryos, resulting in the definition of a narrower ventral domain [15].
• Treatment of pregnant rats with inhibitors of 7-DHC reductase, either AY9944 or BM15.766, has provided a valuable model to study the pathogenesis in SLOS [16].
• Removal of lipoprotein fraction from culture media corrects the reduction of acid sphingomyelinase activity induced by AY9944 [17].

Analytical, diagnostic and therapeutic context of AY-9944

• Neonatal treatment of Long-Evans Hooded rats with the cholesterol synthesis inhibitor (CSI) AY9944 has been shown to increase occurrence of spike-waves in EEG recordings and decrease benzodiazepines sensitivity of GABA(A) receptor-mediated responses in neurons from the thalamic reticular nuclei (nRt, Wu et al., 2004) [18].
• Inhibition of DNA synthesis occurred if AY9944 was added at the early stages of blast transformation but not when the response was well established [14].

References