Action of diphenylamine carboxylate derivatives, a family of non-steroidal anti-inflammatory drugs, on [Ca2+]i and Ca2+-activated channels in neurons

Department of Physiology, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Neuroscience Letters (Impact Factor: 2.03). 06/1995; 190(2):121-4. DOI: 10.1016/0304-3940(95)11518-2
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Ca(2+)-activated channels, including Ca(2+)-activated non-selective (CAN) channels and Ca(2+)-activated Cl- channels play important roles in regulating the electrical activity of neurons. No blockers of neuronal CAN channels have been previously reported. We used 2-electrode voltage clamping to measure membrane currents and fura-2 fluorescence imaging to measure [Ca2+]i in molluscan neurons. We show that the diphenylamine carboxylate derivative flufenamate (FFA), but not mefenamate or the parent compound, cause a transient increase in ICAN and a slow outward current, and a maintained increase in [Ca2+]i. We interpret this as a FFA-dependent release of Ca2+ from intracellular stores and Ca2+ influx, [Ca2+]i-dependent activation of the CAN and slow outward currents, and slow FFA-dependent channel block.

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Available from: Lloyd Donald Partridge, May 04, 2015
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    • "" The LDAP was abolished by bath infusion of 50 ␮M flufenamic acid (FFA). This concentration of FFA has been routinely used to block nonspecific cationic currents (Shaw et al., 1995; Partridge and Valenzuela 2000 "
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    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2004; 24(9):2172-81. DOI:10.1523/JNEUROSCI.4891-03.2004 · 6.34 Impact Factor
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    • "Another important application of DPA is its use as an antioxidant for various polymers and elastomers and as condensates for the insulation of rubber. Some further applications include: (i) DPA as precursor for the chemical synthesis of (azo-)dyes such as Metanil Yellow and Orange IV (Layer and Kehe, 1981; Shao and Young, 1994; Lye and Freeman, 1999), (ii) DPA as stabilizer in perfumery products (Calnan, 1978; Bazin et al., 1986), (iii) its use for the detection of oxidizers (Sugihara et al., 1993), (iv) its use for the detection of DNA (Decallonne and Weyns, 1976; Gendimenico et al., 1988; Thompson and Dvorak, 1989; Hauser and Karamata, 1992), (v) its use as a biozid against body louse, chiggers and housefly (Layer and Kehe, 1981), and (vi) its use as a precursor of non-steroidal antiinflammatory drugs (Shaw et al., 1995; Masubuchi et al., 1999). 4-Amino-DPA (4A-DPA; see Fig. 1C with B ¼ –NH 2 ) is used in the production of hair dyes and other dyes (Singh et al., 1986, 1992), is a precursor and intermediate for the synthesis of various chemicals for photography and for pharmaceutical products (Layer and Kehe, 1981; Srivastava et al., 1982; Lye and Freeman, 1999), and is used in rubber compound manufacture (Layer and Kehe, 1981). "
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    ABSTRACT: Diphenylamine (DPA) is a compound from the third European Union (EU) list of priority pollutants. It was assigned by the EU to Germany to assess and control its environmental risks. DPA and derivatives are most commonly used as stabilizers in nitrocellulose-containing explosives and propellants, in the perfumery, and as antioxidants in the rubber and elastomer industry. DPA is also widely used to prevent post-harvest deterioration of apple and pear crops. DPA is a parent compound of many derivatives, which are used for the production of dyes, pharmaceuticals, photography chemicals and further small-scale applications. Diphenylamines are still produced worldwide by the chemical industries. First reports showed that DPA was found in soil and groundwater. Some ecotoxicological studies demonstrated the potential hazard of various diphenylamines to the aquatic environment and to bacteria and animals. Studies on the biodegradability of DPA and its derivatives are very sparse. Therefore, further investigation is required to determine the complete dimension of the potential environmental hazard and to introduce possible (bio)remediation techniques for sites that are contaminated with this class of compounds. This is the first detailed review on DPA and some derivatives summarizing their environmental relevance as it is published in the literature so far and this review will recommend conducting further research in the future.
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    • "In the rat DHNs, the amplitude and/or the duration of the plateau potential were strongly reduced when most of extracellular Na ϩ was replaced by impermeable molecules through the CAN channels (NMDG or choline), or during superfusion with the specific I CAN blocker FFA. FFA, one member of a class of nonsteroidal anti-inflammatory drugs, was shown to affect two calcium-activated conductances in neurons of the snail Helix aspersa (Shaw et al., 1995). It induced a transient increase in I CAN and in a calcium-activated chloride current, consecutive to a rise in intracellular calcium concentration; subsequently, it blocked the two calcium-activated conductances. "
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    ABSTRACT: Approximately 28% of dorsal horn neurons (DHNs) in lamina V of the rat spinal cord generate voltage-dependent plateau potentials underlying accelerating discharges and prolonged afterdischarges in response to steady current pulses or stimulation of nociceptive primary afferent fibers. Using intracellular recordings in a transverse slice preparation of the cervical spinal cord, we have analyzed the ionic mechanisms involved in the generation and maintenance of plateau potentials in lamina V DHNs. Both the accelerating discharges and afterdischarges were reversibly blocked by Mn(2+) and enhanced when Ca(2+) was substituted with Ba(2+). The underlying tetrodotoxin-resistant regenerative depolarization was sensitive to dihydropyridines, being blocked by nifedipine and enhanced by Bay K 8644. Substitution of extracellular Na(+) with N-methyl-D-glucamine or choline strongly decreased the duration of the plateau potential. Loading the neurons with the calcium chelator BAPTA did not change the initial response but clearly decreased the maximum firing frequency and the duration of the afterdischarge. A similar effect was obtained with flufenamate, a specific blocker of the calcium-activated nonspecific cation current (I(CAN)). We conclude that the plateau potential of deep DHNs is supported by both Ca(2+) influx through intermediate-threshold voltage-gated calcium channels of the L-type and by subsequent activation of a CAN current. Ca(2+) influx during the plateau is potentially of importance for pain integration and the associated sensitization in spinal cord.
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