Catabolism of Ap4A and Ap5A by rat brain synaptosomes

Emanuelli, Tatiana; Bonan, Carla Denise; Sarkis, João José Freitas; Battastini, Ana Maria Oliveira

doi:10.1590/s0100-879x1998001200003

Cited by 7 publications

(4 citation statements)

References 16 publications

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“…AP 4 A is found in tears (Pintor et al, 2002), heart, and brain (Emanuelli et al, 1998; Kisselev et al, 1998; Oaknin et al, 2001). Oxidative stress induces synthesis of AP 4 A (Bochner et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration

et al. 2009

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Diadenosine tetraphosphate (AP4A), two adenosine moieties bridged by four phosphates, is an endogenous purinergic ligand found in brain. Previous studies have shown that AP4A reduced neurodegeneration caused by the dopaminergic neurotoxin 6-hydroxydopamine in rat striatum and substantia nigra. The purpose of this study was to determine whether AP4A is protective against methamphetamine (MA) –mediated toxicity. Primary neuronal cultures were prepared from rat embryonic (E14- E15) ventral mesencephalic tissue. Cultures treated with 2 mM MA exhibited decreased tyrosine hydroxylase (TH) immunoreactivity and increased cleaved caspase-3 immunoreactivity and TUNEL labeling. All these changes were lessened by pretreatment with AP4A. The protective effect of AP4A was also found in vivo. Adult Sprague-Dawley rats were injected with AP4A (25 μg/ 20 μl) or vehicle intracerebroventricularly followed by 4 doses of MA (5 or 10 mg/ kg), given subcutaneously every two hours. Administration of MA reduced locomotor activity one day after injection, which was significantly antagonized by the pretreatment with AP4A. Using immunohistochemical analysis, TH fiber density at the substantia nigra pars reticulata was found reduced while cleaved caspase-3 immunoreactivity in striatum was increased after MA treatment; these responses were also significantly antagonized by AP4A. Taken together, our data show that AP4A has protective effects against MA-mediated toxicity both in vitro and in vivo. The mechanism of action involves suppression of MA -induced apoptosis.

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Section: Introductionmentioning

confidence: 99%

Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration

et al. 2009

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“…Diadenosine polyphosphates (AP n As) are a group of compounds that contain two adenosine moieties bridged by three to six phosphates. Diadenosine tetraphosphate (AP 4 A), a major representative of AP n As, has been found to be highly concentrated in tears (Pintor et al, 2002), and it may be involved in extracellular and intracellular signaling in the brain (Oaknin et al, 2001;Emanuelli et al, 1998;Kisselev et al, 1998). AP 4 A is stored in secretory granules with ATP and can be released after stimulation in a Ca 2ϩ -dependent manner (Pivorun and Nordone, 1996) and during insults or oxidative stress (Bochner et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Diadenosine Tetraphosphate Protects against Injuries Induced by Ischemia and 6-Hydroxydopamine in Rat Brain

et al. 2003

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Diadenosine tetraphosphate (AP4A), an endogenous diadenosine polyphosphate, reduces ischemic injury in the heart. In this study, we report the potent and protective effects of AP4A in rodent models of stroke and Parkinson's disease. AP4A, given intracerebroventricularly before middle cerebral artery (MCA) ligation, reduced cerebral infarction size and enhanced locomotor activity in adult rats. The intravenous administration of AP4A also induced protection when given early after MCA ligation. AP4A suppressed terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) induced by hypoxia/reperfusion in primary cortical cultures, and reduced both ischemia-induced translocation of mitochondrial cytochrome c and the increase in cytoplasmic caspase-3 activity in vivo. The purinergic P2/P4 antagonist di-inosine pentaphosphate or P1-receptor antagonist sulfonylphenyl theophylline, but not the P2-receptor antagonist suramin, antagonized the effect of AP4A, suggesting that the observed protection is mediated through an anti-apoptotic mechanism and the activation of P1- and P4-purinergic receptors. AP4A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehicle-treated rats exhibited amphetamine-induced rotation. Minimal tyrosine hydroxylase immunoreactivity was detected in the lesioned nigra or striatum. No KCl-induced dopamine release was found in the lesioned striatum. All of these indices of dopaminergic degeneration were attenuated by pretreatment with AP4A. In addition, AP4A reduced TUNEL in the lesioned nigra 2 d after 6-OHDA administration. Collectively, our data suggest that AP4A is protective against neuronal injuries induced by ischemia or 6-OHDA through the inhibition of apoptosis. We propose that AP4A may be a potentially useful target molecule in the therapy of stroke and Parkinson's disease.

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“…Primary cleavage of Ap n As is asymmetric, generating AMP and Ap n‐1 from Ap n A. Cellular systems analyzed include blood [19], the adrenal medulla [20], vascular endothelial cells [21,22], synaptic membranes [23,24], airway epithelia [25], and Xenopus oocytes [26].…”

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Hydrolysis of diadenosine polyphosphates by nucleotide pyrophosphatases/phosphodiesterases

Vollmayer

Clair

Goding

et al. 2003

European Journal of Biochemistry

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Diadenosine polyphosphates (Ap n As) act as extracellular signaling molecules in a broad variety of tissues. They were shown to be hydrolyzed by surface-located enzymes in an asymmetric manner, generating AMP and Ap n-1 from Ap n A. The molecular identity of the enzymes responsible remains unclear. We analyzed the potential of NPP1, NPP2, and NPP3, the three members of the ecto-nucleotide pyrophosphatase/phosphodiesterase family, to hydrolyze the diadenosine polyphosphates diadenosine 5¢,5¢¢¢-P 1 ,P 3 -triphosphate (Ap 3 A), diadenosine 5¢,5¢¢¢-P 1 ,P 4 -tetraphosphate (Ap 4 A), and diadenosine 5¢,5¢¢¢-P 1 ,P 5 -pentaphosphate, (Ap 5 A), and the diguanosine polyphosphate, diguanosine 5¢,5¢¢¢-P 1 ,P 4 -tetraphosphate (Gp 4 G). Each of the three enzymes hydrolyzed Ap 3 A, Ap 4 A, and Ap 5 A at comparable rates. Gp 4 G was hydrolyzed by NPP1 and NPP2 at rates similar to Ap 4 A, but only at half this rate by NPP3. Hydrolysis was asymmetric, involving the a,b-pyrophosphate bond. Ap n A hydrolysis had a very alkaline pH optimum and was inhibited by EDTA. Michaelis constant (K m ) values for Ap 3 A were 5.1 lM, 8.0 lM, and 49.5 lM for NPP1, NPP2, and NPP3, respectively. Our results suggest that NPP1, NPP2, and NPP3 are major enzyme candidates for the hydrolysis of extracellular diadenosine polyphosphates in vertebrate tissues.Keywords: diadenosine polyphosphate; diguanosine polyphosphate; ectonucleotidase; nucleotide pyrophosphatase; nucleotide phosphodiesterase.Diadenosine polyphosphates [adenosine-(5¢)-oligophospho-(5¢)-adenosines, Ap n As] comprise two adenosine residues linked together by a polyphosphate chain through phosphoester bonds at their ribose 5¢ carbons. Ap n As are present intracellularly in prokaryotic and eukaryotic cells [1]. Recently, this group of nucleotides has attracted considerable interest because its members act as extracellular signaling molecules in a broad variety of tissues [2,3]. They are involved, for example, in the modulation of synaptic transmission and sensory nerve function [2-4], inhibition of platelet aggregation [5], or in the control of vascular tone [6][7][8][9]. Vasoactive effects were also observed with adenosine polyphosphoguanosines (Ap n Gs) and diguanosine polyphosphates (Gp n Gs) [10].The diadenosine polyphosphates diadenosine 5¢,5¢¢¢-P 1 ,P 3 -triphosphate (Ap 3 A), diadenosine 5¢,5¢¢¢-P 1 ,P 4 -tetraphosphate (Ap 4 A), and diadenosine 5¢,5¢¢¢-P 1 ,P 5 -pentaphosphate (Ap 5 A) are stored in chromaffin granules at millimolar concentrations together with noradrenaline and other nucleotides such as ATP and ADP [11,12]. In cholinergic synaptic vesicles, Ap 4 A and Ap 5 A were found to be co-stored with acetylcholine [13]. They can be released from secretory cells in a stimulus-dependent manner [2]. Besides the adrenal medulla, platelets are thought to represent the main source of Ap n As in blood. Stimulated platelets release, from their storage granules, a mixture of Ap n As (up to Ap 7 A), as well as Ap n Gs and Gp n Gs, together with ATP, ADP and serotonin [14,15]. Ap n ...

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Catabolism of Ap4A and Ap5A by rat brain synaptosomes

Cited by 7 publications

References 16 publications

Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration

Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration

Diadenosine Tetraphosphate Protects against Injuries Induced by Ischemia and 6-Hydroxydopamine in Rat Brain

Hydrolysis of diadenosine polyphosphates by nucleotide pyrophosphatases/phosphodiesterases

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