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Publications (11)28.24 Total impact

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    ABSTRACT: In primary cultures of rat cerebral cortex, N-methyl-D-aspartate causes widespread neurotoxicity. Inhibitors of the nitric oxide generating the enzyme nitric oxide synthase has been shown to attenuate the effects of N-methyl-D-aspartate in a number of neuronal systems both in vivo and in vitro. In our experiments, the nitric oxide synthase inhibitor N-nitroarginine was ineffective at blocking neurotoxicity induced by N-methyl-D-aspartate. Cyclic guanine monophosphate, known to be synthesized in response to nitric oxide was demonstrably inhibited by identical treatments with N-nitroarginine in sister cultures. We conclude that although nitric oxide is produced in response to N-methyl-D-aspartate, it is neither necessary nor sufficient for neurotoxicity.
    Neuroreport 12/1993; 5(2):148-50. DOI:10.1097/00001756-199311180-00013 · 1.52 Impact Factor
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    ABSTRACT: A series of novel spiroisoindolines was designed and synthesized as potential noncompetitive NMDA antagonists. Affinities of these compounds for the noncompetitive NMDA binding site were determined using [3H]TCP and found to possess IC50s ranging from 0.065 to 17μM. In vivo testing of 2′-methylspiro-[4,5,6,7-tetrahydrobenzothiophene-4,1′-(1,3-dihydroisoindole)] (43) showed it to antagonize NMDA-induced convulsions, to be neuroprotective in a gerbil model of ischemia, and not to generalize to MK-801 in a drug discrimination paradigm.
    Bioorganic & Medicinal Chemistry Letters 01/1993; 3(1):55-60. DOI:10.1016/S0960-894X(00)80091-8 · 2.42 Impact Factor
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    ABSTRACT: Quisqualate is a potent neurotoxin in cortical cultures of the rat. Unlike N-methyl-D-aspartate (NMDA), the toxicity of quisqualate is due to overstimulation of a membrane receptor after the agonist has been removed. This receptor appears to be the 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor since 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) are potent antagonists when added to the post incubation media. NBQX and DNQX are ineffective when present only during quisqualate exposure, indicating the AMPA receptor is not involved in the initial event. Transfer of culture media 30 min after quisqualate exposure to either neuronal or non-neuronal cells was found to cause toxicity in previously untreated neuronal cells. This effect could not be reproduced with NMDA. The neurotoxic chain of events could be interrupted during quisqualate exposure by removal of sodium from the incubation media, suggesting the involvement of a sodium-dependent plasma membrane uptake mechanism. Quisqualate may be continually recycled by internalization and release, causing neurotoxicity by persistent stimulation of the AMPA receptor.
    European Journal of Pharmacology 04/1992; 212(2-3):129-36. DOI:10.1016/0014-2999(92)90320-4 · 2.53 Impact Factor
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    ABSTRACT: Ibotenic acid (Ibo) has been shown to have agonist activity at both theN-methyl-d-aspartate (NMDA) andtrans-ACPD or metabolotropic quisqualate (Qm) receptor sites in several systems. Both of these receptor sites have been implicated in excitotoxicity. Like NMDA neurotoxicity, Ibo neurotoxicity can be enhanced by glycine and blocked by MK-801. Ibo induced stimulation of phosphoinositide (PI) hydrolysis, on the other hand, is unaffected by either of these treatments. We therefore conclude that Ibo is capable of acting at both NMDA andtrans-ACPD receptors in the CNS, although only activation of NMDA receptors is involved in Ibo neurotoxicity. This conclusion leads us to postulate that stimulation of phosphoinositide hydrolysis is neither necessary nor sufficient for neurotoxicity.
    Neurochemical Pathology 02/1992; 16(1):1-10. DOI:10.1007/BF03159956
  • W. Craig Moore · Helen M. Hargrove · Andre I. Salama · Jitendra Patel ·
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    ABSTRACT: Using fura-2 loaded neural tumour cells, SK-N-SH, we demonstrate that receptor-mediated activation of phosphoinositide hydrolysis not only causes the release of Ca2+ from intracellular stores but also causes a concomitant influx of extracellular Ca2+. Thapsigargin (TG), a sesquiterpene lactone, causes a sustained elevation of intracellular Ca2+ and depletion of the inositol 1, 4, 5-trisphosphate-sensitive intracellular Ca2+ stores. In the absence of extracellular Ca2+, the increase in intracellular Ca2+ concentration ([Ca2+]i) was transient, suggesting that thapsigargin activates both intracellular mobilization and the influx of Ca2+ from extracellular space. These results are consistent with the proposal that the depletion of the inositol 1, 4, 5-trisphosphate-sensitive intracellular Ca2+ pool serves as a signal for Ca2+ influx.
    Neuroreport 04/1991; 2(3):124-6. DOI:10.1097/00001756-199103000-00003 · 1.52 Impact Factor
  • Jitendra Patel · Richard A. Keith · Andre I. Salama · W. Craig Moore ·
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    ABSTRACT: Using primary neuronal cultures we have examined the role of extracellular Ca2+ in a receptor-regulated phosphoinositide turnover. We report that receptor (glutamic acid and acetylcholine)-activated phosphoinositide turnover requires the presence of extracellular Ca2+ (EC50 = 21.1 microM). The requirement for Ca2+ appears to be at an intracellular level and is highly selective for Ca2+. We also found that several inorganic and organic Ca2+ channel blockers, including La3+ and verapamil, inhibit phosphoinositide turnover. However, the pharmacological profile of these agents in this regard was distinct from their actions at the voltage-sensitive Ca2+ channels. To explain the above requirement for extracellular Ca2+ in agonist-stimulated phosphoinositide turnover and its sensitivity to Ca(2+)-channel blockers, we propose a hypothetical model suggesting that Ca2+, following IP-3-mediated mobilization, exerts a facilitatory action on the activity of receptor-phospholipase C complex. We further propose that in the absence of extracellular Ca2+ or in the presence of certain Ca(2+)-channel blockers, refilling of calciosomes is ineffectual or inhibited, causing its depletion and subsequent inactivation of agonist-stimulated phosphoinositide turnover.
    Journal of Molecular Neuroscience 02/1991; 3(1):19-27. DOI:10.1007/BF02896845 · 2.34 Impact Factor
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    ABSTRACT: The effects of inhibitors of voltage-sensitive calcium channels (VSCC) on K(+)-evoked [3H]D-aspartate release from rat hippocampal slices and the K(+)-evoked increase in intracellular calcium in neocortical neurons in primary culture were examined. K+ caused a concentration-dependent release of [3H]D-aspartate that was approximately 85% dependent on the presence of extracellular calcium. Neither the marine snail toxin, omega-conotoxin GVIA, nor the dihydropyridine VSCC antagonist, nitrendipine, had any effect on K(+)-evoked release of [3H]D-aspartate. omega-Conotoxin GVIA and nitrendipine caused a relatively small (20-30%) inhibition of K(+)-evoked increase in intracellular calcium in neocortical neurons in primary culture. This suggests that K(+)-evoked [3H]D-aspartate release is not dependent on L- or N-type VSCC, whereas K(+)-evoked neuronal calcium influx was only partially dependent on L- and N-type VSCC. Verapamil, dextromethorphan and diltiazem caused a concentration-dependent inhibition of K(+)-evoked release of [3H]D-aspartate with IC50 values of 30, 100 and 120 microM, respectively. The K(+)-evoked increase in intracellular calcium was inhibited with essentially the same rank order of potency, but with slightly greater potencies (IC50 values for verapamil, diltiazem and dextromethorphan were 20, 50 and 50 microM, respectively). At 300 microM, neither verapamil, diltiazem nor dextromethorphan inhibited [3H]D-aspartate release evoked by the calcium ionophore ionomycin, suggesting that these compounds are not acting intracellularly to inhibit the ability of free cytosolic calcium to evoke release.(ABSTRACT TRUNCATED AT 250 WORDS)
    European Journal of Pharmacology 02/1991; 192(1):9-17. DOI:10.1016/0014-2999(91)90062-U · 2.53 Impact Factor
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    ABSTRACT: Based on radioligand binding and electrophysiological studies, quinoxalinediones such as 6,7-dinitroquinoxaline-2,3-dione (DNQX) have been shown to be potent competitive antagonists at the quisqualate and kainate subtypes of the glutamate receptor. In this report we have examined the effects of DNQX on excitatory amino acid neurotoxicity and evoked neurotransmitter release. DNQX was found to be a potent neuroprotective agent against glutamate and N-methyl-D-aspartate (NMDA) neurotoxicity. The data suggest that this neuroprotective activity of DNQX is due to its antagonism of the coagonist activity of glycine at the NMDA receptor-channel complex. The specificity of DNQX for the glycine site associated with the NMDA receptor-channel complex was confirmed in radioligand binding and neurotransmitter release studies. DNQX also prevented kainate neurotoxicity and kainate-evoked neurotransmitter release, presumably by direct competition for the kainate receptor. DNQX, however, did not prevent quisqualate neurotoxicity, suggesting that a novel quisqualate-preferring receptor insensitive to DNQX may mediate quisqualate toxicity.
    Journal of Neurochemistry 08/1990; 55(1):114-21. DOI:10.1111/j.1471-4159.1990.tb08828.x · 4.28 Impact Factor
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    ABSTRACT: Activation of phosphoinositide metabolism is an early event in signal transduction for a number of neurotransmitters and hormones. In primary cultures of rat neurocortical cells, various excitatory amino acids stimulate inositol phosphate production with a rank order of potency of quisqualate > ibotenate > glutamate > kainate, N-methyl-d-aspartate > -amino-3-hydroxyl-5-methyl-4-isoxazole propionate. This response to excitatory amino acids was insensitive to a variety of excitatory amino acid antagonists including 6-cyano-7-nitroquinoxaline-2,3-dione, 3–3(2-carboxypiperazine-4-yl)propyl-l-phosphonate, and 2-amino-4-phosphonobutyrate. The individual responses of quisqualate-, ibotenate-, and kainate-stimulated inositol phosphate production were not additive. These results suggest that phosphoinositide metabolism activated by excitatory amino acids is mediated by a unique quisqualate-preferring receptor that is not antagonized by known N-methyl-d-aspartate and non-N-methyl-d-aspartate antagonists, and is relatively insensitive to -amino-3-hydroxyl-5-methyl-4-isoxazole propionate.
    Journal of Neurochemistry 04/1990; 54(5):1461 - 1466. DOI:10.1111/j.1471-4159.1990.tb01192.x · 4.28 Impact Factor
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    ABSTRACT: Current evidence indicates that glutamate acting via the N-methyl-D-aspartate (NMDA) receptor/ion channel complex plays a major role in the neuronal degeneration associated with a variety of neurological disorders. In this report the role of glycine in NMDA neurotoxicity was examined. We demonstrate that NMDA-mediated neurotoxicity is markedly potentiated by glycine and other amino acids, e.g., D-serine. Putative glycine antagonists HA-966 and 7-chlorokynurenic acid were highly effective in preventing NMDA neurotoxicity, even in the absence of added glycine. The neuroprotective action of HA-966 and 7-chlorokynurenic acid, but not that of NMDA antagonists 3-(2-carboxypiperazine-4-yl)propylphosphonate and MK-801, could be reversed by glycine. These results indicate that glycine, operating through a strychinine-insensitive glycine site, plays a central permissive role in NMDA-mediated neurotoxicity.
    Journal of Neurochemistry 04/1990; 54(3):849-54. DOI:10.1111/j.1471-4159.1990.tb02329.x · 4.28 Impact Factor
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    ABSTRACT: The role of endogenous glycine in supporting N-methyl-D-aspartate (NMDA)-evoked neurotransmitter release was investigated. HA-966 (1-hydroxy-3-aminopyrrolidone-2) inhibited NMDA-evoked release of [3H]norepinephrine from rat hippocampal brain slices, but was much less effective in inhibiting [3H]norepinephrine release evoked by kainic acid (KA). Glycine (1 mM) reversed the HA-966 (1 mM) antagonism of NMDA-evoked release of [3H]norepinephrine. Strychnine (10 microM) had no effect on the ability of glycine to reverse HA-966 antagonism of NMDA-evoked neurotransmitter release. Other amino acids were also capable of reversing the HA-966 antagonism of NMDA-evoked [3H]norepinephrine release with a rank order of potency: D-serine greater than or equal to glycine much greater than L-serine approximately beta-alanine. These same compounds inhibited strychnine-insensitive [3H]glycine binding to rat cortical membrane fragments with a rank order of potency: glycine greater than D-serine much greater than L-serine greater than or equal to beta-alanine. In addition, HA-966 inhibited [3H]glycine binding (IC50 = 8.5 microM). The results suggest that HA-966 antagonism of NMDA-evoked neurotransmitter release is due to the inhibition of endogenous glycine acting at a strychnine-insensitive modulatory glycine site associated with the NMDA receptor/ionophore complex.
    European Journal of Pharmacology 09/1989; 166(3):393-400. DOI:10.1016/0014-2999(89)90351-8 · 2.53 Impact Factor