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S A Lipton

Publications and source records attributed to S A Lipton.

At least 109 records · Page 6Linked to original sources
PubMed1995

Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function.

During ischemic brain injury, glutamate accumulation leads to overstimulation of postsynaptic glutamate receptors with intracellular Ca2+ overload and neuronal cell death. Here we show that glutamate can induce either early necrosis or delayed apoptosis in cultures of cerebellar granule cells. During and shortly after exposure to glutamate, a subpopulation of neurons died by necrosis. In these cells, mitochondrial membrane potential collapsed, nuclei swelled, and intracellular debris were scattered in the incubation medium. Neurons surviving the early necrotic phase recovered mitochondrial potential and energy levels. Later, they underwent apoptosis, as shown by the formation of apoptotic nuclei and by chromatin degradation into high and low molecular weight fragments. These results suggest that mitochondrial function is a critical factor that determines the mode of neuronal death in excitotoxicity.

Animals↗
PubMed1995

Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain.

A novel NMDA receptor-like (NMDAR-L) cDNA was isolated that contained an open reading frame coding for a predicted polypeptide of 1115 amino acids that shares approximately 27% identity with NMDA receptor subunits. In situ hybridization experiments indicated that NMDAR-L mRNA was expressed in the developing rodent CNS. On postnatal day 1 (P1), NMDAR-L mRNA expression was pronounced in the entorhinal cortex, the subiculum and the thalamus, in layer V of the developing neocortex, in the superior and inferior colliculi, and various regions of the hindbrain, excluding the cerebellum. On P5, NMDAR-L mRNA was expressed in layer V of the neocortex, in the entorhinal cortex, in the subiculum, and in the thalamus. On P14, NMDAR-L mRNA was expressed in layers II-VI of the neocortex, in the entorhinal and piriform cortex, in the subiculum and CA1 field, and in the nucleus of the lateral olfactory tract. In the adult brain, NMDAR-L mRNA was detected predominately in the nucleus of the lateral olfactory tract. Injection of NMDAR-L cRNA into Xenopus oocytes did not lead to the expression of homomeric glutamate-activated channels. However, coinjection of the triple combination of NMDAR-L with NMDAR1 and NMDAR2B cRNAs led to a striking decrease in the current magnitude compared to currents obtained after coexpression of the double combination of NMDAR1 with NMDAR2B. While the function of NMDAR-L remains to be established, its developmental and regional expression pattern suggests that NMDAR-L may influence axonal outgrowth and synaptogenesis during brain development.

Aging↗
PubMed1995

Multiple GABA receptor subtypes mediate inhibition of calcium influx at rat retinal bipolar cell terminals.

Inhibitory effects of GABA on K(+)-evoked Ca2+ influx into rat retinal bipolar cell terminals were studied using calcium imaging methods. Application of high K+ evokes a sustained, reversible increase in [Ca2+]i at bipolar cell terminals, which occurs mainly via dihydropyridine-sensitive (L-type) Ca2+ channels. There are at least two GABA receptor subtypes coexisting at bipolar cell terminals: a conventional GABAA receptor and a bicuculline/baclofen-insensitive GABA receptor. Activation of either GABA receptor inhibited the K(+)-evoked Ca2+ response. However, these two GABA receptor subtypes have distinct properties. GABAA receptors suppress the Ca2+ response only at relatively high concentrations of agonist, and with fas kinetics and a narrow dynamic range. In contrast, the bicuculline/baclofen-insensitive GABA receptors produce inhibition on the Ca2+ response at a much lower concentration of agonist, and with slow onset and a wider dynamic range. The pharmacologic profile of the bicuculline/baclofen-insensitive GABA receptor at bipolar cell terminals is most similar to the GABAC receptor reported by Feigenspan et al. (1993). Unlike the GABAC receptors described in other species, it is extremely insensitive to picrotoxin. Therefore, it may be appropriate to refer to this receptor as a picrotoxin-insensitive GABAc receptor. 3-Aminopropyl(methyl)phosphinic acid (3-APMPA) and 3-aminopropylphosphonic (3-APA), two phosphate analogs of GABA, selectively antagonize the picrotoxin-insensitive GABAc receptors but not the GABAA receptors in this system. These results imply a functional role for multiple GABA receptors in regulating synaptic transmission at bipolar cell terminals.

Animals↗
PubMed1995

Differential modulation by sulfhydryl redox agents and glutathione of GABA- and glycine-evoked currents in rat retinal ganglion cells.

Some areas of the mammalian CNS, such as the retina, contain not one but two fast inhibitory neurotransmitter systems whose actions are mediated by GABA and glycine. Each inhibitory receptor system is encoded by a separate gene family and has a unique set of agonists and antagonists. Therefore, in rat retinal ganglion cells we were surprised to find that a single agent, extracellular glutathione, was capable of modulating currents activated by either GABAA or glycine receptor stimulation. Both oxidized and reduced glutathione influence inhibitory neurotransmission in a manner similar to that of the sulfhydryl redox agents dithiothreitol (DTT) and 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB). Remarkably, the actions of glutathione are diametrically opposed on the GABAA and glycine systems. In whole-cell recordings of single retinal ganglion cells with patch pipettes, reduced glutathione enhances GABA-evoked currents but decreases glycine-evoked currents. These findings suggest that endogenous redox agents, such as glutathione, may constitute a novel modulatory system for the differential regulation of inhibitory neurotransmission in the mammalian retina.

Animals↗
PubMed1994

AIDS-related dementia and calcium homeostasis.

Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.

AIDS Dementia Complex↗
PubMed1994

Greater sensitivity of larger retinal ganglion cells to NMDA-mediated cell death.

Glutamate toxicity in retinal ganglion cells has well documented both in vitro and in vivo, and has been suggested to play a role in the neuronal loss in glaucoma. Of note, glaucoma selectively damages larger retinal ganglion cells first, and we therefore sought to explore whether glutamate-mediated cell death was likewise more pronounced in larger retinal ganglion cells. We now report that glutamate--which exerts its toxic effect on neurons predominantly through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor--is more toxic to larger retinal ganglion cells both in tissue culture and in the intact rat eye. Cells smaller than 10 microns were relatively unaffected by glutamate or NMDA. These agents are, however, markedly toxic to retinal ganglion cells larger than 10 microns. These observations indicate that glutamate-mediated loss is seen first in larger retinal ganglion cells, in a similar fashion to the pattern of loss seen in glaucoma.

Animals↗
PubMed1994

The neuropathogenesis of HIV-1 infection.

HIV infection in brain revolves around productive viral replication in cells of mononuclear phagocyte lineage, including brain macrophages, microglia, and multinucleated giant cells [1-4]. Together, they are the investigators for cellular and viral neurotoxic activities [5-10]. Several published reports show that viral and/or cellular products produced from HIV-1-infected macrophages injure neurons and induce glial proliferation during advancing central nervous system (CNS) infection [11-18]. These findings are supported by the apparent discrepancy between the distribution and numbers of virus-infected cells and concomitant brain tissue pathology [5, 19]. Whether these soluble factors are indirectly responsible for neuronal damage remains undefined. The identification and regulation of neurotoxins produced from HIV-infected macrophages are central to uncovering how HIV mediates CNS disease. The authors who contributed to this work represent laboratories with overlapping areas of expertise. Broad-based complementary hypotheses regarding HIV neuropathogenesis are now provided.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Actions of redox-related congeners of nitric oxide at the NMDA receptor.

The local redox milieu of a biological system is of critical importance in understanding the actions of the nitrogen monoxide (NO) moiety, as disparate chemical pathways involving distinct redox-related congeners of NO may trigger neurotoxic or neuroprotective pathways. The reactions of nitric oxide (NO.) with superoxide can lead to neurotoxicity through formation of peroxynitrite, whereas NO. alone does not, at least under certain conditions. Reaction (or transfer) of NO+ equivalents to thiol(s) on the NMDA receptor can lead to neuroprotection by inhibiting Ca2+ influx. These findings suggest that cell function can be controlled by, or through, protein S-nitrosylation, and raise the possibility that the NO group may initiate signal transduction in or at the plasma membrane. Neuroprotective effects of NO- suggest that acceleration of disulfide bond formation at the NMDA receptor is of mechanistic importance in the attenuation of Ca2+ influx. Our findings suggest novel therapeutic strategies. For example, downregulation of NMDA receptor activity can be obtained via sulfhydryl oxidation by S-nitros(yl)ation with NO+ donors (to form an RSNO at a cysteine residue on the receptor), or with NO- donors (with intermediate formation of RSNHOH). Pharmacologic intervention with these forms of NO donors could be implemented in the treatment of focal ischemia, neuropathic pain, Huntington's disease, AIDS dementia, and other neurological disorders associated, at least in part, with excessive activation of NMDA receptors.

Animals↗
PubMed1994

Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor.

Modulation of NMDA-mediated responses by oxidizing and reducing reagents has been described in a variety of neuronal preparations. Here, we report that NMDA-gated currents of oocytes expressing heteromeric NMDA receptors are also modulated by sulfhydryl redox reagents. Each cysteine residue in the NMDAR1 (NR1) subunit and each conserved NMDAR2 (NR2) cysteine residue in a prototypical subunit (NR2B) was tested for its role in redox modulation. We have identified 2 cysteines in the NR1 subunit that are required for redox modulation of NMDA-gated currents in oocytes expressing NR1-NR2B, NR1-NR2C, or NR1-NR2D receptors. Mutation of these same 2 cysteines also eliminated potentiation by spermine and shifted the IC50 for H+ inhibition and the EC50 for NMDA. Redox modulation of heteromeric NR1-NR2A receptors appeared to be different from that of the other heteromeric receptors, indicating the presence of one or more unique redox modulatory sites on NR1-NR2A receptors.

Animals↗
PubMed1994

Nitric oxide in the central nervous system.

1. The reactions of nitric oxide with superoxide can lead to neurotoxicity through formation of peroxynitrite, and not by NO. alone, at least under our conditions. 2. Transfer of NO+ groups to thiol(s) on the NMDA receptor can lead to neuroprotection by inhibiting Ca2+ influx. These findings suggest that cell function can be controlled by, or through, protein S-nitrosylation, and raise the possibility that the NO group may initiate signal transduction in or at the plasma membrane. 3. The local redox milieu of a biological system is of critical importance in understanding NO actions as disparate chemical pathways involving distinct redox related congeners of NO may trigger neurotoxic or neuroprotective pathways. These claims are highlighted in the CNS by the recent finding that tissue concentrations of cysteine approach 700 microM in settings of cerebral ischemia (Slivka and Cohen, 1993); these levels of thiol would be expected to influence the redox state of the NO group. 4. Finally, our findings suggest novel therapeutic strategies. For example, downregulation of NMDA receptor activity via S-nitrosylation with NO+ donors could be implemented in the treatment of focal ischemia, AIDS dementia, and other neurological disorders associated, at least in part, with excessive activation of NMDA receptors.

Animals↗
PubMed1994

Update on current models of HIV-related neuronal injury: platelet-activating factor, arachidonic acid and nitric oxide.

This review aims to summarize recent work related to the pathogenesis and possible treatment of neuronal injury in the acquired immunodeficiency syndrome (AIDS), especially with reference to potential neurotoxic substances released by HIV-infected or gp120-stimulated macrophages/microglia. Approximately a third of adults and half of children with AIDS eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews recent evidence suggesting that at least part of the neuronal injury observed in the brains of AIDS patients is related to excessive influx of Ca2+ after the release of potentially noxious substances from HIV-infected or gp120-stimulated macrophages/microglia. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, i.e. arachidonic acid and its metabolites, as well as platelet-activating factor. Other candidate toxins include nitric oxide (NO.), superoxide anion (O2.-), and the N-methyl-D-aspartate (NMDA) agonist, cysteine. Similarly, macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites, and cysteine.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS Dementia Complex↗
PubMed1994

Neuronal injury associated with HIV-1 and potential treatment with calcium-channel and NMDA antagonists.

A substantial number of adults and half of the children with acquired immunodeficiency syndrome (AIDS) suffer from neurological manifestations. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss, although neurons themselves do not appear to be infected by HIV-1. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells, especially after interacting with astrocytes, secrete neurotoxic substances. Not all of these substances are yet known, but they may include eicosanoids, platelet-activating factor, quinolinate, cysteine, cytokines, and free radicals. Macrophages activated by HIV-1 envelope protein gp120 also appear to release similar toxins. Some of these factors can lead to increased glutamate release or decreased glutamate reuptake. A final common pathway for neuronal suceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-asparate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.

AIDS Dementia Complex↗