Allopregnanolone (ALLO), is a brain endogenous neurosteroid that binds with high affinity to ␥-aminobutyric acid type A (GABAA) receptors and positively modulates the action of GABA at these receptors. Unlike ALLO, 5␣-dihydroprogesterone (5␣-DHP) binds with high affinity to intracellular progesterone receptors that regulate DNA transcription. To investigate the physiological roles of ALLO and 5␣-DHP synthesized in brain, we have adopted a mouse model involving protracted social isolation. In the frontal cortex of mice, socially isolated for 6 weeks, both neurosteroids were decreased by approximately 50%. After administration of (17␤)-17-(bis-1-methyl amino carbonyl) androstane-3,5-diene-3-carboxylic acid (SKF105,111), an inhibitor of the enzyme (5␣-reductase Type I and II) that converts progesterone into 5␣-DHP, the ALLO and 5␣-DHP content of frontal cortex of both grouphoused and socially isolated mice decreased exponentially to 10%-20% of control values in about 30 min. The fractional rate constants (k h ؊1 ) of ALLO and 5␣-DHP decline multiplied by the ALLO and 5␣-DHP concentrations at any given steady-state estimate the rate of synthesis required to maintain that steady state. After 6 weeks of social isolation, ALLO and 5␣-DHP biosynthesis rates were decreased to 30% of the values calculated in grouphoused mice. Moreover, in socially isolated mice, the expression of 5␣-reductase Type I mRNA and protein was approximately 50% lower than in group-housed mice whereas 3␣-hydroxysteroid oxidoreductase mRNA expression was equal in the two groups. Protracted social isolation in mice may provide a model to investigate whether 5␣-DHP by a genomic action, and ALLO by a nongenomic mechanism down-regulate the action of drugs acting as agonists, partial agonists, or positive allosteric modulators of the benzodiazepine recognition sites expressed by GABAA receptors.A llopregnanolone (ALLO), (3␣5␣-tetrahydroprogesterone), and 5␣-dihydroprogesterone (5␣-DHP) are the most likely candidates among the endogenous neuroactive steroids for a neurophysiological role in maintaining GABAergic transmission efficacy. ALLO is synthesized in brain from progesterone by the sequential action of two enzymes: (i) 5␣-reductase, which reduces progesterone to 5␣-DHP; and (ii) 3␣-hydroxysteroidoxidoreductase (3␣-HSOR), which either converts 5␣-DHP into ALLO (reductive reaction) or converts ALLO into 5␣-DHP (oxidative reaction) (1, 2).Several lines of evidence have demonstrated that these neurosteroids in nanomolar concentrations regulate GABAergic transmission by two modalities: (i) nongenomic (ALLO), by facilitating ␥-aminobutyric acid (GABA) gating of GABA type A (GABA A ) receptors after ALLO-specific binding to an allosteric center expressed by these receptors; and (ii) genomic (5␣-DHP) by regulating DNA transcription, perhaps including genes encoding for GABA A receptor subunits, after 5␣-DHP binding to intracellular progesterone receptors (3, 4).The influence of these neurosteroids on the physiological efficacy of GABA A receptor function ...

No abstract

No abstract

Three autopsied cases of dissecting aneurysms with spontaneous subarachnoid hemorrhage of the intracranial posterior circulation are reported, and the literature is reviewed to investigate the pathological characteristics and pathogenesis of this lesion. The location and pathological features of the aneurysms were different in each of the cases presented. Subadventitial hemorrhage associated with the subarachnoid hemorrhage, multiple noncontiguous intramural hemorrhages, and new vessels in and around the arterial wall were noteworthy findings in our series. All 20 reported autopsied cases of the vertebrobasilar artery have a dissection between the media and adventitia with a rupture site in the thin adventitia. Seventeen of them had disruption of the entire arterial wall, but the remaining three cases had no apparent luminal connection. The clinicopathological features of this disease are various. On the basis of the pathological investigations of these reported cases, the pathogenesis of this lesion is discussed. Intramural hemorrhage associated with dissection without luminal connection should not be disregarded as a causative factor.

A convenient new method for synthesizing queuine (1 ) (2-amino-5-[ (1 S,2R,3S)-2,3-dihydroxycyclopent-4-enylaminomethyl]pyrrolo [2,3-d]pyrimidin-4(3H)-one}, the base of the naturally occurring hypermodified nucleoside, queuosine, present in certain transfer RNAs, and its biosynthetic precursor, 2-amino-5-aminomethyIpyrrolo[2,3-~ pyrimidin-4(3H) -one (2) (Pre Q1 base), was successfully exploited. This method involved two critical reactions: the Mannich reaction using dibenzylamine-formaldehyde of 2-acylaminopyrrolo[2,3-d]pyrimidin-4(3H)-one (7), which resulted in the selective introduction of the dibenzylaminomethyl group into the 5-position of (7), and an amine exchange reaction of the 5-dibenzylamino function in the resulting Mannich base (1 7) with (1 S,2Rr3S) -2,3-isopropylidenedioxycyclopent-4-enylamine, which yielded the desired queuine (1). Similar reaction of (17) with ammonia gave the biosynthetic precursor of queuine (2) (Pre Q1 base). Thus, a series of queuine analogues with structural variations in their 5-aminomethyl side-chains was synthesized b y the amine exchange reaction of (17) with appropriate amines or b y acylation of (2) with appropriate acylating agents.is the base of a hypermodified nucleoside, queuosine, located in the first position of the anticodon of tRNA molecules from various organisms, including mammalian tissues. Because of its unique structure and particular biosynthesis, much attention has been focussed on its biological function in cells, tissues, and whole mammals. ' Its functional role, however, remains to be clarified.The present study was initiated in order to obtain a sample, sufficient in amount to allow further extensive biological studies of (1) ' The first total syntheses of queuosine, queuine, and its biosynthetic precursor,2 pre Q 1 base (2) (2-amino-5-aminomethylpyrrolo[2,3-d]-pyrimidin-4(3H)-one), were achieved by Goto et ~1 . ~ However, their methods of synthesis, although elegant, require extremely lengthy and multistep procedures which are inefficient when synthesizing large quantities of (1) and its analogues for extensive biological studies.