Low‐Level Hyperbaric Antagonism of Ethanol's Anticonvulsant Property in C57BL/6J Mice

Davies, Daryl L.; Mørland, Jörg; Jones, Brenda L.; Alkana, Ronald L.

doi:10.1111/j.1530-0277.1994.tb00103.x

Cited by 12 publications

(21 citation statements)

References 36 publications

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“…In marked contrast to this action in mature neurons, activation of GABA A R by GABA or APα in immature neurons, leads to an efflux of chloride. The high intracellular chloride content in embryonic cells, reverses the concentration gradient for chloride whereby the efflux of chloride leads to depolarization of the membrane and opening of VGLCC [25,28,51,52]. Blockade of APα-induced neurogenesis by an inhibitor of VGLCC is consistent with our finding of an APα-induced rise in intracellular calcium via activation of VGLCC [15].…”

Section: Mechanism Of Apα-induced Neurogenesissupporting

confidence: 86%

Preclinical Analyses of the Therapeutic Potential of Allopregnanolone to Promote Neurogenesis In Vitro and In Vivo in Transgenic Mouse Model of Alzheimers Disease

Brinton

Wang²

2006

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Herein, we present data to support a preclinical proof of concept for the therapeutic potential of allopregnanolone to promote neurogenesis. Our recent work has demonstrated that the neuroactive progesterone metabolite, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), (APalpha) induced, in a dose dependent manner, a significant increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural stem cells (hNSM) derived from the cerebral cortex [1]. Proliferative efficacy was determined by incorporation of BrdU and (3)H-thymidine, FACS analysis of MuLV-GFP-labeled mitotic NPCs and quantification of total cell number. Allopregnanolone-induced proliferation was isomer and steroid specific, in that the stereoisomer 3beta-hydroxy-5beta-pregnan-20-one and related steroids did not increase (3)H-thymidine uptake. Immunofluorescent analyses for the NPC markers, nestin and Tuj1, indicated that newly formed cells were of neuronal lineage. Furthermore, microarray analysis of cell cycle genes and real time RT-PCR and western blot validation revealed that allopregnanolone increased the expression of genes which promote mitosis and inhibited the expression of genes that repress cell proliferation. Allopregnanolone-induced proliferation was antagonized by the voltage gated L-type calcium channel blocker nifedipine consistent with the finding that allopregnanolone induces a rapid increase in intracellular calcium in hippocampal neurons via a GABA type A receptor activated L-type calcium channel. Preliminary in vivo data indicate that APalpha for 24 hrs significantly increased neurogenesis in dentate gyrus, as determined by unbiased stereological analysis of BrdU positive cells, of 3-month-old male triple transgenic Alzheimer's disease mice. The in vitro and in vivo neurogenic properties of APalpha coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of toxicity, are key elements required for developing APalpha as a neurogenic / regenerative therapeutic for restoration of neurons in victims of Alzheimer's disease.

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Section: Mechanism Of Apα-induced Neurogenesissupporting

confidence: 86%

Preclinical Analyses of the Therapeutic Potential of Allopregnanolone to Promote Neurogenesis In Vitro and In Vivo in Transgenic Mouse Model of Alzheimers Disease

Brinton

Wang²

2006

CAR

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“…The antagonism occurred without measurable changes in baseline behavior, CNS or receptor excitability (Bejanian et al . 1993; Davies et al . 1994; Syapin et al .…”

Section: Discussionmentioning

confidence: 99%

Multiple sites of ethanol action in α1 and α2 glycine receptors suggested by sensitivity to pressure antagonism

Davies

Crawford

Trudell

et al. 2004

Journal of Neurochemistry

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The current study used an ethanol antagonist, increased atmospheric pressure, to test the hypothesis that ethanol acts on multiple sites in glycine receptors (GlyRs). The effects of 12 times normal atmospheric pressure of helium-oxygen gas (pressure) on ethanol-induced potentiation of GlyR function in Xenopus oocytes expressing human a1, a2 or the mutant a1(A52S) GlyRs were measured using two-electrode voltage clamp. Pressure reversibly antagonized potentiation of glycine in a1 GlyR by 40-200 mM ethanol, but did not antagonize 10 and 25 mM ethanol in the same oocytes. In contrast, pressure did not significantly affect potentiation of glycine by 25-100 mM ethanol in a2 GlyRs, nor did pressure alter ethanol response in the A52S mutant. Pressure did not affect baseline receptor function or response to glycine in the absence of ethanol. These findings provide the first direct evidence for multiple sites of ethanol action in GlyRs. The sites can be differentiated on the basis of ethanol concentration, subunit and structural composition and sensitivities to pressure antagonism of ethanol. Parallel studies with butanol support this conclusion. The mutant a1(A52S) GlyR findings suggest that increased attention should be focused on the amino terminus as a potential target for ethanol action.

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“…Further studies of the involvement of the GlyR EC domain in ethanol action have taken advantage of the pharmacological phenomenon that increased atmospheric pressure (pressure) acts as a direct mechanistic antagonist to ethanol. Pressures up to 12 times normal antagonized the behavioral and biochemical actions of ethanol (Alkana and Malcolm, 1981; Alkana et al, 1992; Bejanian et al, 1993; Davies and Alkana, 1998, 2001) without altering ethanol pharmacokinetics, behavioral or electrophysiological baselines, or CNS excitation (Davies et al, 1994, 1999; Syapin et al, 1996). Thus, if a GlyR site is involved in ethanol modulation, mutating it should alter the effects of pressure as well as ethanol.…”

Section: Glycine Receptors: Defining Alcohol Binding Through Mutagenementioning

confidence: 99%

Alcohol-Binding Sites in Distinct Brain Proteins: The Quest for Atomic Level Resolution

Howard

Slesinger

Davies

et al. 2011

Alcoholism: Clinical and Experimental Research

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Defining the sites of action of ethanol on brain proteins is a major prerequisite to understanding the molecular pharmacology of this drug. The main barrier to reaching an atomic-level understanding of alcohol action is the low potency of alcohols, ethanol in particular, which is a reflection of transient, low-affinity interactions with their targets. These mechanisms are difficult or impossible to study with traditional techniques such as radioligand binding or spectroscopy. However, there has been considerable recent progress in combining X-ray crystallography, structural modeling, and site-directed mutagenesis to define the sites and mechanisms of action of ethanol and related alcohols on key brain proteins. We review such insights for several diverse classes of proteins including inwardly rectifying potassium, transient receptor potential, and neurotransmit-ter-gated ion channels, as well as protein kinase C epsilon. Some common themes are beginning to emerge from these proteins, including hydrogen bonding of the hydroxyl group and van der Waals interactions of the methylene groups of ethanol with specific amino acid residues. The resulting binding energy is proposed to facilitate or stabilize low-energy state transitions in the bound proteins, allowing ethanol to act as a “molecular lubricant” for protein function. We discuss evidence for characteristic, discrete alcohol-binding sites on protein targets, as well as evidence that binding to some proteins is better characterized by an interaction region that can accommodate multiple molecules of ethanol.

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Low‐Level Hyperbaric Antagonism of Ethanol's Anticonvulsant Property in C57BL/6J Mice

Cited by 12 publications

References 36 publications

Preclinical Analyses of the Therapeutic Potential of Allopregnanolone to Promote Neurogenesis In Vitro and In Vivo in Transgenic Mouse Model of Alzheimers Disease

Preclinical Analyses of the Therapeutic Potential of Allopregnanolone to Promote Neurogenesis In Vitro and In Vivo in Transgenic Mouse Model of Alzheimers Disease

Multiple sites of ethanol action in α1 and α2 glycine receptors suggested by sensitivity to pressure antagonism

Alcohol-Binding Sites in Distinct Brain Proteins: The Quest for Atomic Level Resolution

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