Death by a dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP) and protection by EGF in GH3 cells

In this study we investigated the uptake and effect of a dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP⁺) on a clonal strain, GH3 cells, established from rat anterior pituitary. Although the level was very low compared with that in PC12 cells, a clonal rat pheochromocytoma cell line, there was a detectable amount of tyrosine hydroxylase protein in GH3 cells. The levels of monoamines including dopamine in GH3 cells were also very low compared with those in PC12 cells.

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was incorporated to GH3 cells in a concentration-dependent manner and the uptake was inhibited by nomifensine, an inhibitor of dopamine transporter. Addition of 200 μM MPP⁺ stimulated the leakage of lactate dehydrogenase (LDH) after a lag of 24 h. Pretreatment with 50 ng/ml of epidermal growth factor (EGF), but not nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF), protected against MPP⁺-induced cell death. These findings show that: (1) MPP⁺ uptake to GH3 cells was via an effective dopamine transport system and causes delayed cell death, and (2) EGF protects against MPP⁺-induced cell death. A possible role for GH3 cells as dopaminergic neurons is discussed.     

Apoptosis in alpha interferon (IFN-α) intratumoral chemotherapy for cystic craniopharyngiomas

Objectives

The aim of this study was to verify whether intracystic injections of alpha-Interferon (IFN-α) in cystic craniopharyngiomas were able to reduce the tumor by activating the Fas apoptotic pathway.

Materials and methods

Twenty-one patients with cystic craniopharyngiomas treated at the Pediatric Oncology Institute (IOP/GRAACC) of Federal University of São Paulo were submitted to intracystic chemotherapy with IFN-α. The tumor sizes of all patients were monitored and the apoptotic factor soluble FasL (sFasL) concentration was determined by ELISA (enzyme-linked immunosorbent assay) in tumor fluid samples from eight patients.

Results

There was a complete reduction in 11 patients, a partial response in seven, and a minor response in three patients. The concentration of sFasL was increased in all the eight patients examined concomitantly with the tumor size reduction.

Conclusions

Our data demonstrated that the IFN-α was able to induce Fas-mediated apoptosis together with a reduction in the tumor size; such an observation may suggest the importance to investigate still unexplored mechanisms to be exploited in craniopharyngioma therapy.

     

K-current modulated by PO2 in type I cells in rat carotid body is not a chemosensor

According to the membrane channel hypothesis of carotid body O₂ chemoreception, hypoxia suppresses K⁺ currents leading to cell depolarization, [Ca²⁺]_i rise, neurosecretion, increased neural discharge from the carotid body. We show here that tetraethylammonium (TEA) plus 4-aminopyridine (4-AP) which suppressed the Ca²⁺ sensitive and other K⁺ currents in rat carotid body type I cells, with and without low [Ca²⁺]_o plus high [Mg²⁺]_o, did not essentially influence low

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effects on [Ca²⁺]_i and chemosensory discharge. Thus, hypoxia may suppress the K⁺ currents in glomus cells but K⁺ current suppression of itself does not lead to chemosensory excitation. Therefore, the hypothesis that K⁺–O₂ current is linked to events in chemoreception is not substantiated. K⁺–O₂ current is an epiphemenon which is not directly linked with O₂ chemoreception.     

Surgical resection plus stereotactic <Superscript>125</Superscript>I brachytherapy in adult patients with eloquently located supratentorial WHO grade II glioma – Feasibility and outcome of a combined local treatment concept

Objective

The current pilot study analyzed feasibility, risk and effectiveness of 1) microsurgery plus stereotactic iodine-125 (¹²⁵I) brachytherapy (SBT) for large (diameter > 4 cm), circumscribed, and complex located WHO grade II glioma and 2) SBT alone for small (diameter < 4 cm), and complex located recurrences.

Methods

Lowactivity temporary ¹²⁵I seeds were used. The applied reference dose was 54 Gy and the dose rate was low (median, 10 cGy/h). Time to progression and time to additional external beam radiation (EBR) and/or chemotherapy were estimated with the Kaplan-Meier method. Any adverse sequel potentially attributable to treatment was classified as morbidity. Treatment effects of SBT were estimated according to the modified MacDonald criteria.

Results

Thirtyone patients (de novo group: n = 18, recurrence group: n = 13) were included. The median tumor volume before surgery was 66 ml. A planned partial tumor resection achieved eligibility for SBT in all patients. Transient morbidity of microsurgery and SBT was 27.8 % and 6.4 %, respectively. There was no permanent morbidity. Radiogenic complications did not occur. Complete response, partial response, and stable disease were seen in 8, 9, and 14 patients, respectively. Ten patients exhibited tumor progression (overall 5-year progression- free survival > 60 %). The 5-year probability to receive chemotherapy and/or EBR was 18 %.

Conclusion

A planned partial tumor resection of large and complex located WHO grade II glioma is safe. SBT of small and complex located residual of recurrent tumors is safe and minimally invasive. Combined treatment may provide the possibility to withhold EBR and/or chemotherapy for a considerable number of patients and deserves further prospective evaluation.

     

Modulatory effect of

Summary Detailed neuropathologic and immunohistologic analysis of a case of serologically and polymerase chain reaction-confirmed human immunodeficiency virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is reported in a 73-year-old North American black woman. In addition to the usual neuropathologic features of HAM/TSP, including tractal degeneration of the spinal cord, leptomeningeal and perivascular fibrosis, perivascular demyelination and chronic inflammation, neuroaxonal spheroids were prominent in the spinal cord. Neuroaxonal dystrophy was characterized by neurofilamentous masses that were immunoreactive for phosphorylated neurofilament epitopes, but not ubiquitin. Neuroimmunologic analysis of the inflammatory reaction revealed a prevalence of CD8⁺ T cells and class I major histocompatibility molecules (MHC) (HLA-ABC and 2-microglobulin), but very few CD4⁺ T cells. Microglia were highly reactive for class II MHC (HLA-DR) and this was attributed to activation, rather than CD4 interaction, since CD4 presence was minimal. Inflammatory cytokine immunoreactivity was also detected in glia. It is concluded that the cumulative effects of cytotoxic T cell (CD8) infiltration and the possible involvement of cytokines were responsible for the unusual degree of neuroaxonal dystrophy and vascular fibrosis, as well as the observed demyelination in this case.Supported in part by grants NS 07098, NS 08952, NS 11920 and MH 47667 from the NIH; and RG 1001-G-7 from the National Multiple Sclerosis Society.     

Neuroaxonal dystrophy in HTLV-1-associated myelopathy/tropical spastic paraparesis: neuropathologic and neuroimmunologic correlations

Summary Detailed neuropathologic and immunohistologic analysis of a case of serologically and polymerase chain reaction-confirmed human immunodeficiency virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is reported in a 73-year-old North American black woman. In addition to the usual neuropathologic features of HAM/TSP, including tractal degeneration of the spinal cord, leptomeningeal and perivascular fibrosis, perivascular demyelination and chronic inflammation, neuroaxonal spheroids were prominent in the spinal cord. Neuroaxonal dystrophy was characterized by neurofilamentous masses that were immunoreactive for phosphorylated neurofilament epitopes, but not ubiquitin. Neuroimmunologic analysis of the inflammatory reaction revealed a prevalence of CD8⁺ T cells and class I major histocompatibility molecules (MHC) (HLA-ABC and 2-microglobulin), but very few CD4⁺ T cells. Microglia were highly reactive for class II MHC (HLA-DR) and this was attributed to activation, rather than CD4 interaction, since CD4 presence was minimal. Inflammatory cytokine immunoreactivity was also detected in glia. It is concluded that the cumulative effects of cytotoxic T cell (CD8) infiltration and the possible involvement of cytokines were responsible for the unusual degree of neuroaxonal dystrophy and vascular fibrosis, as well as the observed demyelination in this case.Supported in part by grants NS 07098, NS 08952, NS 11920 and MH 47667 from the NIH; and RG 1001-G-7 from the National Multiple Sclerosis Society.     

Neuronal activity patterns in the ventral thalamus: Comparison between Parkinson’s disease and cervical dystonia

Objective

The aim of this study was to distinguish neuronal activity patterns in the human ventral thalamus and reveal common and disease-specific features in patients with Parkinson’s disease (PD) and cervical dystonia (CD).

Activation of protein kinase C by phorbol dibutyrate potentiates [

Since ATP has been reported to be a potent excitatory transmitter in the mammalian central nervous system (CNS), we studied the neurochemical characters of the binding sites of

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,

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-methylene ATP, an agonist of P_2X receptors, in mouse crude synaptic membranes. ATP and its related compounds inhibited [³H]

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,

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-methylene ATP binding in a concentration-dependent manner. The potency order in the inhibition of the binding was as follows;

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,

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-methylene

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>

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> ATP ≥ ADP >

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,

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-methylene ATP UTP > 2-methylthio ATP. And adenosine did not affect the binding. The order was different from those reported in peripheral tissues. And Sr²⁺, Ca²⁺, Mg²⁺, and Cd²⁺ enhanced the binding. These results suggest that

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,

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-methylene ATP binding sites in CNS have different characters from those in peripheral tissues.     

Characterization of α,β-Methylene ATP Binding Sites in Mouse Crude Synaptic Membranes

Since ATP has been reported to be a potent excitatory transmitter in the mammalian central nervous system (CNS), we studied the neurochemical characters of the binding sites of

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,

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-methylene ATP, an agonist of P_2X receptors, in mouse crude synaptic membranes. ATP and its related compounds inhibited [³H]

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,

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-methylene ATP binding in a concentration-dependent manner. The potency order in the inhibition of the binding was as follows;

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,

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-methylene

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>

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> ATP ≥ ADP >

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,

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-methylene ATP UTP > 2-methylthio ATP. And adenosine did not affect the binding. The order was different from those reported in peripheral tissues. And Sr²⁺, Ca²⁺, Mg²⁺, and Cd²⁺ enhanced the binding. These results suggest that

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,

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-methylene ATP binding sites in CNS have different characters from those in peripheral tissues.     

The regulation of dopamine release from striatum slices by tetrahydrobiopterin and l-arginine-derived nitric oxide

The regulation of dopamine release by 6(R)-tetrahydrobiopterin (BH₄) and

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-arginine-derived nitric oxide was examined by using a method of superfusion of rat striatum slices in vitro.

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-Arginine, which can produce nitric oxide (NO) through the action of NO synthase, induces a concentration-dependent increase of [

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] dopamine release in the superfusate of striatum slices. Pretreatment with inhibitors of NO synthase or with inhibitors of BH₄ synthesis diminishes the increase of [

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] dopamine release mediated by arginine. This increase is almost completely restored following repletion of intracellular BH₄ levels by incubation of the slices with 7,8-dihydrobiopterin. Adding exogenous BH₄ directly to the superfusion fluid leads to a massive increase in [

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] dopamine release which can be inhibited 75% by superoxide dismutase and catalase, but is not inhibited by N^G-nitro-arginine, a NO synthase inhibitor, or alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. The increase of intracellular BH₄ concentration by dihydrobiopterin administration causes a small increase of dopamine release which can be partially diminished by N^G-nitro-arginine or alpha-methyl-p-tyrosine. It is suggested that the increase of dopamine release stimulated by an enhancement of intracellular BH₄ is dependent on its cofactor activity with NO synthase and tyrosine hydroxylase. This study has also demonstrated that BH₄ is a regulator of NO-mediated dopamine release in the striatum.     

l-DOPA neurotoxicity is mediated by glutamate release in cultured rat striatal neurons

The exposure of cultured rat striatal neurons to

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-DOPA caused marked cell death. The

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-DOPA cytotoxicity was inhibited by the addition of Mg²⁺ to and by the removal of Ca²⁺ from the culture medium, and also by the application of tetrodotoxin. Moreover, prolonged application of

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-DOPA increased the glutamate content in the culture medium. These results indicate that

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-DOPA produces neurotoxicity by facilitating glutamate release.     

Selective impairments of alerting and executive control in HIV-infected patients: evidence from attention network test

Background

Attention ability can be subdivided into three functionally independent networks, i.e., alerting network, orienting network, and executive network. Previous literature has documented that deficits in attention are a common consequence of HIV infection. However, the precise nature of deficits of attention in HIV-infected patients is poorly understood. Accordingly, the aim of the study was to identify whether the HIV-infected patients showed a specific attention network deficit or a general attentional impairment.

Methods

We investigated 27 HIV-infected patients and 31 normal controls with the Attention Network Test (ANT).

Results

The patients exhibited less efficient alerting network and executive network than controls. No significant difference was found in orienting network effect between groups. Our results also indicate a tendency for poorer efficiency on alerting attention and executive attention in patients with CD4 ≤ 200.

Conclusions

Our findings suggest that HIV-infected patients exhibited selective impairments of attention network of alerting and executive control. The link between lower CD4 T cell count and poorer attention network function imply the importance of starting antiretroviral therapy earlier to avoid irreversible neurocognitive impairment.

     

Sustained pharmacological inhibition of nitric oxide synthase does not affect the survival of intrastriatal rat fetal mesencephalic transplants

The objective of the present study was to investigate the potential role of the free radical nitric oxide (NO) in the development of fetal rat mesencephalic neurons grafted in a 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease. First, using nitric oxide synthase (NOS)-immunocytochemistry and reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry, we investigated the presence of the neuronal isoform of NOS (nNOS) in intrastriatal mesencephalic grafts. During the course of the experiment (16 weeks) an increase in the staining intensity and the number of nNOS/NADPH-d positive cells within the grafts was observed, as well as a gradual maturation of dopaminergic neurons. In addition, within both the host striatal and grafted mesencephalic tissue, a NO-dependent accumulation of cyclic guanosine monophosphate (cGMP) was detected, indicating the presence of guanylate cyclase, i.e., the target-enzyme for NO. Secondly, to determine the impact of NO on the survival of grafted dopaminergic neurons, 6-OHDA lesioned rats received mesencephalic grafts and were subsequently treated with the competitive NOS-inhibitor N^ω-nitro-

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-arginine methylester (

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-NAME). After chronic treatment for 4 weeks, tyrosine hydroxylase immunocytochemistry revealed no apparent differences between the survival of grafted dopaminergic neurons in control- or

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-NAME treated animals, respectively. As the maturation of grafted dopaminergic neurons coincides with a gradual increase in the expression of nNOS within the graft and since dopaminergic cell numbers are not changed upon administration of

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-NAME, it is concluded that endogenously produced and potentially toxic NO does not affect the survival of grafted fetal dopaminergic neurons.     

Phosphorylation of the Third Intracellular Loop of the Mouse α1b-Adrenergic Receptor by cAMP-dependent Protein Kinase

The third intracellular loop of adrenergic receptors has been implicated in their interaction with guanine nucleotide-binding proteins (G proteins). One of the mechanisms involved in the modulation of receptor function is the phosphorylation of specific residues by intracellular kinases.

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-Adrenergic receptor is phosphorylated in vitro by cAMP-dependent protein kinase (PKA), although its physiological effect remains to be determined. We have produced fusion proteins formed by glutathione S-transferase and sequences of the third intracellular loop of mouse

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-,

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-, and

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-adrenergic receptor subtypes, and used them as substrates for PKA. Only the fusion protein containing the

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sequence was phosphorylated in vitro by this kinase. Site-directed mutagenesis of a serine (homologue to serine 278 of the rat sequence, RSS) to an alanine residue precluded phosphorylation by PKA.     

The symptoms of autonomic dysfunction in HIV-positive Africans

Background

Human immunodeficiency virus (HIV) infection is associated with autonomic neuropathy. The resultant autonomic dysfunction impairs quality of life and can have fatal consequences. Our aim was to clearly define the symptoms of autonomic dysfunction in African HIV-positive patients and determine whether these symptoms were related with (a) autonomic reflex responses (b) the degree of immunosupression.

Methods

Thirty-one HIV-positive treatment-naïve African patients (mean CD4 cell count 269.5 ± 253.4/mm³) and 12 healthy controls completed a detailed questionnaire (Autonomic System Profile, Mayo Clinic, Rochester, MN) relating to specific symptoms of autonomic dysfunction. After completion of the questionnaire, subjects underwent a standard battery of autonomic reflex tests.

Results

The autonomic symptom score was higher in the male HIV-positive patients (26.7 ± 14.7 points) and female patients with CD4 <200/mm³ (24.7 ± 18.0) than sex-matched controls (male controls, 9.9 ± 6.8, P < 0.05; female controls, 8.8 ± 10.1; P < 0.05). Six patients had scores indicative of severe autonomic dysfunction (>43.8 points). The most common autonomic symptoms were: orthostatic intolerance, secretomotor and gastrointestinal dysfunction. There was no relationship between CD4 cell counts and autonomic symptom scores. The blood pressure response to sustained handgrip was blunted, but all other cardiovascular reflex tests were within the normal range or borderline.

Conclusion

African HIV-positive patients report symptoms of autonomic dysfunction, despite normal or borderline autonomic reflex responses.

     

Intracellular acidification induced by membrane depolarization in rat hippocampal slices: roles of intracellular Ca and glycolysis

To elucidate the mechanism of pH_i changes induced by membrane depolarization, the variations in pH_i and [Ca²⁺]_i induced by a number of depolarizing agents, including high K⁺, veratridine, N-methyl-

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-aspartate (NMDA) and ouabain, were investigated in rat hippocampal slices by the fluorophotometrical technique using BCECF or fura-2. All of these depolarizing agents elicited a decrease in pH_i and an elevation of intracellular calcium ([Ca²⁺]_i) in the CA1 pyramidal cell layer. The increases in [Ca²⁺]_i caused by the depolarizing agents almost completely disappeared in the absence of Ca²⁺ (0 mM Ca²⁺ with 1 mM EGTA). In Ca²⁺ free media, pH_i acid shifts produced by high K⁺, veratridine or NMDA were attenuated by 10–25%, and those produced by ouabain decreased by 50%. Glucose-substitution with equimolar amounts of pyruvate suppressed by two-thirds the pH_i acid shifts induced by both high K⁺ and NMDA. Furthermore, lactate contents were significantly increased in hippocampal slices by exposure to high K⁺, veratridine or NMDA but not by ouabain. These results suggest that the intracellular acidification produced by these depolarizing agents, with the exception of ouabain, is mainly due to lactate accumulation which may occur as a result of accelerated glycolysis mediated by increased Na⁺–K⁺ ATPase activity. A Ca²⁺-dependent process may also contribute to the intracellular acidification induced by membrane depolarization. Since an increase in H⁺ concentration can attenuate neuronal activity, glycolytic acid production induced by membrane depolarization may contribute to the mechanism that prevents excessive neuronal excitation.     

Inhibition of regulatory volume decrease in swollen rat primary astrocyte cultures by methylmercury is due to increased amiloride-sensitive Na uptake

Primary astrocyte cultures from neonatal rats were swollen by exposure to hypotonic buffer with and without 10 μM methylmercury (MeHg). We investigated the effects of MeHg on K⁺ (using ⁸⁶Rb), taurine,

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-aspartate (a non metabolizable analogue of glutamate) and Na⁺ fluxes during regulatory volume decrease (RVD), with an electrical impedance method for determination of cell volume, coupled with on-line measurements of efflux of radioactive ions and amino acids. Addition of 10 μM MeHg completely inhibited RVD in swollen astrocytes, increased the uptake of ²²Na⁺, increased ⁸⁶Rb release, and decreased ³H-taurine release. There was no effect on the rate of release of ³H-

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-aspartate from swollen astrocytes. 0.5 mM amiloride completely inhibited MeHg-induced increased Na⁺ influx during RVD, while 1 mM furosemide had no effect. When Na⁺ in the hypotonic buffer was replaced with N-methyl-

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-glucamine (NMDG), RVD in the presence of MeHg was indistinguishable from controls. These results indicate that MeHg increases cellular permeability to ions such as Na⁺ and K⁺, and that an increase in Na⁺ permeability via Na⁺/H⁺ exchange, offsetting K⁺ loss, is the primary mechanism in its inhibition of RVD in swollen astrocytes.     

The Effect of μ-Opioid Receptor Antisense on Morphine Potency and Antagonist-Induced Supersensitivity and Receptor Upregulation

The present study examined the effect of in vivo antisense oligodeoxynucleotide treatment on naltrexone (NTX)-induced functional supersensitivity and

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-opioid receptor upregulation in mice. On day 1 mice were implanted SC with a NTX or placebo pellet and injected IT and ICV with dH₂O or oligodeoxynucleotides. The oligodeoxynucleotides were designed so that they were either perfectly complementary to the first 18 bases of the coding region of mouse

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-opioid receptor mRNA, or had one (Mismatch-1) or four (Mismatch-4) mismatches. On days 3, 5, 7, and 9, mice were again injected IT and ICV with dH₂O or one of the oligodeoxynucleotides. After the final injections on day 9, placebo and NTX pellets were removed, and 24 h later mice were tested for morphine analgesia or sacrificed for saturation binding studies ([³H]DAMGO). Naltrexone increased the analgesic potency of morphine in dH₂O treated mice by ≈ 70%. In binding studies, NTX significantly increased density of brain (≈ 60%) and spinal cord (≈ 140%)

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-opioid receptors without affecting affinity. The

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-opioid antisense and the oligodeoxynucleotide with one mismatch (Mismatch-1) significantly reduced the potency of morphine by ≈ twofold in placebo-treated mice. The oligodeoxynucleotide with four mismatches (Mismatch-4) did not significantly alter morphine potency. When placebo-treated mice were treated with either the antisense to the mouse

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-opioid receptor, Mismatch-4 or Mismatch-1 there were no significant changes in the density of

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-opioid receptors. Thus,

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-opioid antisense significantly reduced morphine potency without changing

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-opioid receptor density. When NTX and oligodeoxynucleotide treatments were combined, there was no change in NTX-induced supersensitivity and

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-opioid receptor upregulation. These data suggest that opioid antagonist-induced supersensitivity and upregulation of

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-opioid receptors does not involve changes in gene expression.     

Role of perforin secretion from CD8+ T-cells in neuronal cytotoxicity in multiple sclerosis

Objectives: Multiple sclerosis (MS) is the most prevalent autoimmune disease of the central nervous system, and is characterized by inflammation and myelin damage. The immune system initiates the autoimmune response, although the mechanisms of neuronal damage have not been elucidated. The purpose of the present study was to investigate autoreactive CD4+ and CD8⁺ T lymphocytes, in conjunction with other inflammatory cells and cytokines in active MS lesions.

Methods: EAE animal models was established by plantar injections of MBP (200 μg per rat). Purified CD4+ or CD8+ T-cells were isolated from heparinized peripheral blood (EAE animals and control animals) via negative selection. To examine effects of presence of autoreactive CD4+ and CD8+ T lymphocytes, we carried out ELISA, Western blot analysis and TUNEL. In addition, we examined the direct effects of various factors on neuronal cell death using MTT assay.

Results: The data revealed that CD8+ T-cells were more toxic to neurons compared to CD4+ T-cells, in both the MBP and EAE conditions. Bax was greater increased when neurons were co-cultured with CD8+ T-cells in the MBP group. There is a significant increase in IL-17 secretion by CD4+ T-cells in both the MBP group and EAE group. Neuronal viability were affected by Perforin (1.5 μg/mL).

Conclusion: The present study extends previous research by demonstrating the role of CD8+ T-cells in MS and supports perforin secretion by CD8+ T-cells as a potential therapeutic factor. Furthermore, we determined that CD4⁺ T-cells can enhance CD8⁺ T-cell neuronal cytotoxicity via induction of intense inflammation.     

Effects of l-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey

We studied the effects of

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-DOPA on the firing patterns of pallidal neurons in experimental parkinsonism. After a unilateral injection of MPTP, we observed a decrease in the firing rate of GPe neurons, and a slight increase in their bursting activity. In the GPi, there was a considerable augmentation of both neuronal firing frequency and the number of bursting cells. During

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-DOPA treatment (10 mg/kg), GPe neurons.pattern is almost unmodified. The firing frequency of GPi neurons, on the contrary, decreased even lower than the control level. A slight reduction was observed in bursting activity. These unexpected results would show that the normalizing effect of

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-DOPA on GPi output is limited.