Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors

Bold, Jane M.; Gardner, Colin; Walker, Robert

doi:10.1111/j.1476-5381.1985.tb16151.x

Cited by 23 publications

(11 citation statements)

References 17 publications

(23 reference statements)

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“…Inosine potentiates adenosine-induced vasodilation of pial arterioles, presumably via inhibition of adenosine uptake (Ngai et al, 1989). Inosine has been shown to produce inhibitory responses in rat cerebellar Purkinje cells (Bold et al, 1985), mouse spinal cord neuronal cultures (MacDonald et al, 1979), rat cortical neurons (Phillis et al, 1975), and guinea~pighippocampal slices (Alzheimer et al, 1991). Inosine"aiso appears to elicit a rapidly desensitizing excitatory response in mouse spinal cord neuronal cultures (MacDonald et al, 1979).…”

Section: Figmentioning

confidence: 99%

Inosine Mediates the Protective Effect of Adenosine in Rat Astrocyte Cultures Subjected to Combined Glucose‐Oxygen Deprivation

Haun¹,

Segeleon²,

Trapp³

et al. 1996

Journal of Neurochemistry

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Preliminary evidence suggests adenosine, a neuromodulator, has neuroprotective properties during cerebral ischemia. It is unclear, however, if adenosine has glioprotective effects. We studied the effect of adenosine on cellular injury in astroglial cultures subjected to combined glucose-oxygen deprivation. Adenosine (100-1,000~tM)dramatically reduced astroglial injury, whereas the adenosine agonists 2-chloroadenosine (10 nM-100 bIM), N 6-cyclopentyladenosine (1 nM-10~.tM),5'-Nethylcarboxamidoadenosine (10 nM-100 1.tM), and N

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Section: Figmentioning

confidence: 99%

Inosine Mediates the Protective Effect of Adenosine in Rat Astrocyte Cultures Subjected to Combined Glucose‐Oxygen Deprivation

Haun¹,

Segeleon²,

Trapp³

et al. 1996

Journal of Neurochemistry

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“…These effects depend on the expression of the GABA A R β3 subunit (Laposky, Homanics, Basile, & Mendelson, 2001), but direct evidence for these compounds binding to the BZ-binding site and activating the GABA A R is lacking. Other small molecule candidate ligands including inosine, hypoxanthine, and nicotinamide have low affinity for the GABA A R BZ-binding site and are present in low concentrations in the brain and thus are unlikely to represent the natural physiological relevant endozepines (Asano & Spector, 1979; Bold, Gardner, & Walker, 1985; Lapin, 1980; Tallman, Paul, Skolnick, & Gallager, 1980). …”

Section: Candidate Endozepinesmentioning

confidence: 99%

Endozepines

Farzampour

Reimer

Huguenard

2015

Advances in Pharmacology

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Since their introduction in the 1960s, benzodiazepines (BZs) remain one of the most commonly prescribed medications, acting as potent sedatives, hypnotics, anxiolytics, anticonvulsants, and muscle relaxants. The primary neural action of BZs and related compounds is augmentation of inhibitory transmission, which occurs through allosteric modulation of the gamma-aminobutyric acid (GABA)-induced current at the gamma-aminobutyric acid receptor (GABAAR). The discovery of the BZ-binding site on GABAARs encouraged many to speculate that the brain produces its own endogenous ligands to this site (Costa & Guidotti, 1985). The romanticized quest for endozepines, endogenous ligands to the BZ-binding site, has uncovered a variety of ligands that might fulfill this role, including oleamides (Cravatt et al., 1995), nonpeptidic endozepines (Rothstein et al., 1992), and the protein diazepam-binding inhibitor (DBI) (Costa & Guidotti, 1985). Of these ligands, DBI, and affiliated peptide fragments, is the most extensively studied endozepine. The quest for the “brain's Valium” over the decades has been elusive as mainly negative allosteric modulatory effects have been observed (Alfonso, Le Magueresse, Zuccotti, Khodosevich, & Monyer, 2012; Costa & Guidotti, 1985), but recent evidence is accumulating that DBI displays regionally discrete endogenous positive modulation of GABA transmission through activation of the BZ receptor (Christian et al., 2013). Herein, we review the literature on this topic, focusing on identification of the endogenous molecule and its region-specific expression and function.

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“…For example, nicotinamide can function as an anxiolytic [128], increase brain choline levels [72], and act as an endogenous ligand for benzodiazepine receptors [129]. Additional work has indicated that nicotinamide can increase cell tolerance against vascular thermal injury and increase capillary density [130].…”

Section: Nicotinamide Progenitor Cells and Cellular Proliferationmentioning

confidence: 99%

Cell Life Versus Cell Longevity: The Mysteries Surrounding the NAD+ Precursor Nicotinamide

Chong²,

Maiese³

2006

CMC

113

167

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Nicotinamide, the amide form of niacin (vitamin B 3 ), is the precursor for the coenzyme β-nicotinamide adenine dinucleotide (NAD + ) and plays a significant role during the enhancement of cell survival as well as cell longevity. Yet, these abilities of nicotinamide appear to be diametrically opposed. Here we describe the development of nicotinamide as a novel agent that is critical for modulating cellular metabolism, plasticity, longevity, and inflammatory microglial function as well as for influencing cellular life span. The capacity of nicotinamide to govern not only intrinsic cellular integrity, but also extrinsic cellular inflammation rests with the modulation of a host of cellular targets that involve mitochondrial membrane potential, poly(ADP-ribose) polymerase, protein kinase B (Akt), Forkhead transcription factors, Bad, caspases, and microglial activation. Further knowledge acquired in regards to the ability of nicotinamide to foster cellular survival and regulate cellular lifespan should significantly promote the development of therapies against a host of disorders, such as aging, Alzheimer's disease, diabetes, cerebral ischemia, Parkinson's disease, and cancer. KeywordsAkt; Alzheimer's disease; apoptosis; caspases; diabetes; erythropoietin; Huntington's disease; microglia; NAD + ; Parkinson's disease; stroke; vitamin B 3 NICOTINAMIDE, NAD + PRECURSOR, AND CELLULAR METABOLISMAs the amide form of niacin or vitamin B 3 , nicotinamide is the precursor for the coenzyme β-nicotinamide adenine dinucleotide (NAD + ) and is essential for the synthesis of nicotinamide adenine dinucleotide phosphate (NADP + ) [1,2]. Nicotinamide and nicotinic acid can be obtained either through synthesis in the body or through a dietary source [3]. The predominant form of niacin in dietary plant sources is nicotinic acid that is rapidly absorbed through the gastrointestinal epithelium. Nicotinamide is formed through the conversion of nicotinic acid in the liver or through the hydrolysis of NAD + . Once nicotinamide is obtained in the body, it is utilized to synthesize NAD + [4].Nicotinamide through NAD + plays a critical physiological role in cellular metabolism and can be directly utilized by cells to synthesize NAD + [4]. Nicotinamide also participates in energy metabolism through the tricarboxylic acid cycle by utilizing NAD + in the mitochondrial respiratory electron transport chain for the production of ATP, DNA synthesis, and DNA repair *Address correspondence to this author at the Department of Neurology, 8C-1 UHC, Wayne State University School of Medicine, 4201 St. Antoine, Detroit, MI 48201, USA; Fax: 313-966-0486; E-mail: kmaiese@med.wayne.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript [5][6][7]. Furthermore, nicotinamide can significantly increase NAD + levels in vulnerable regions of the ischemic brain, suggesting that nicotinamide may offer cytoprotection of injured tissue through the maintenance of NAD + levels [8]. Administration of nicotinamide can signif...

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Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors

Cited by 23 publications

References 17 publications

Inosine Mediates the Protective Effect of Adenosine in Rat Astrocyte Cultures Subjected to Combined Glucose‐Oxygen Deprivation

Inosine Mediates the Protective Effect of Adenosine in Rat Astrocyte Cultures Subjected to Combined Glucose‐Oxygen Deprivation

Endozepines

Cell Life Versus Cell Longevity: The Mysteries Surrounding the NAD+ Precursor Nicotinamide

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