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R J Miller

Publications and source records attributed to R J Miller.

At least 91 records · Page 5Linked to original sources
PubMed1997

Regulation of human neuronal calcium channels by G protein betagamma subunits expressed in human embryonic kidney 293 cells.

We examined the ability of different G protein subunits to inhibit the activity of human alpha1B and alpha1E Ca2+ channels stably expressed in human embryonic kidney (HEK) 293 cells together with beta1B and alpha2Bdelta Ca2+ channel subunits. Under normal conditions, Ca2+ currents in alpha1B-expressing cells showed little facilitation after a depolarizing prepulse. However, when we overexpressed the beta2gamma2 subunits of heterotrimeric G proteins, the time course of activation of the Ca2+ currents was considerably slowed and a depolarizing prepulse produced a large facilitation of the current as well as an acceleration in its time course of activation. Similar effects were not observed when cells were transfected with constitutively active mutants of the G protein alpha subunits alpha s, alpha i1, and alpha o or with the G protein beta2 and gamma2 subunits alone. Studies carried out in cells expressing alpha1E currents showed that overexpression of beta2gamma2 subunits produced pre-pulse facilitation, although this was of lesser magnitude than that observed with Ca2+ currents in alpha1B-expressing cells. The subunits beta2 and gamma2 alone produced no effects, nor did constitutively active alpha s, alpha i1, and alpha o subunits. Phorbol esters enhanced alpha1E Ca2+ currents but had no effect on alpha1B currents, suggesting that protein kinase C activation was not responsible for the observed effects. When alpha1E Ca2+ currents were expressed without their beta subunits, they exhibited prepulse facilitation. These results demonstrate that alpha1E Ca2+ currents are less susceptible to direct modulation by G proteins than alpha1B currents and illustrate the antagonistic interactions between Ca2+ channel beta subunits and G proteins.

Calcium Channels↗
PubMed1997

Histological presence of viable prostatic glands on routine biopsy following cryosurgical ablation of the prostate.

PURPOSE: Cryosurgical ablation of the prostate has recently received much attention as a therapeutic alternative for the treatment of localized prostatic adenocarcinoma. Biopsies after treatment reveal a variety of dysplastic changes as well as unaltered prostatic glandular epithelial elements. Prostate specific antigen (PSA) remains undetectable in the majority of men. However, in some PSA increases without demonstrable local recurrence. MATERIALS AND METHODS: A total of 383 patients underwent 447 procedures between June 1990 and January 1994. Of 358 biopsies performed at our institution, 317 (2,075 cores) were available for review. Each core was examined for unaltered prostatic glandular epithelial elements and then scored for the percentage of epithelial glandular involvement according to a scale of: 0-no, 0.5-less than 10%, 1-10 to 25%, 2-25 to 50%, 3-50 to 75% and 4-76 to 100% unaltered prostatic glandular epithelial elements. RESULTS: Of 317 biopsies 158 (49.8%) contained no unaltered prostatic glandular epithelial elements, while 185 (58.3%) and 206 (65%) had 1 core containing 10% and 10 to 25%, respectively, of such elements. Of 262 cases (82.6%) with a mean of 10% unaltered prostatic glandular epithelial elements per core 22 (8.4%) were positive for residual carcinoma. Among 55 cases with more normal epithelium per core 24 (43.6%) were positive for residual carcinoma. Patients with a positive biopsy had a median PSA of 2.02 ng./ml. (average gland/core score 0.54). Median PSA for men with negative biopsies was 0.2 ng./ml. (gland/core score 0.124). CONCLUSIONS: Cryosurgical ablation of the prostate has the ability to ablate prostatic tissue completely, thus rendering it free of glandular elements as determined by biopsy. Increasing PSA can indicate residual glandular elements. Increases in unaltered prostatic glandular epithelial elements with time are not paralleled by increased rates of local disease recurrence. undetectable serum PSA has a low risk of residual unaltered prostatic glandular epithelial elements and localized carcinoma. Results as measured by unaltered prostatic glandular epithelial elements and PSA improve with the surgical experience.

Adenocarcinoma↗
PubMed1996

Selective G-protein regulation of neuronal calcium channels.

We examined the properties and regulation of Ca channels resulting from the expression of human alpha1B and alpha1E subunits stably expressed in KEK293 cells. The ancillary subunits beta1B and alpha2/delta were also stably expressed in these cell lines. Ca currents in alpha1B-expressing cells had the properties of N-type currents. Ca currents in cells expressing alpha1E exhibited a novel profile that was similar to the properties of the "R type" Ca current. Introduction of GTP-gamma-S into alpha1B cells greatly enhanced the extent of prepulse facilitation of the Ca current, whereas it had only a very small effect in alpha1E-expressing cells. Activation of somatostatin receptors endogenous to HEK293 cells or kappa opioid receptors, expressed in the cells after transfection, inhibited Ca currents in alpha1B-expressing cells. This inhibition was blocked by pertussis toxin and was partially relieved by a depolarizing prepulse. In contrast, no inhibitory effects were noted in cells expressing alpha1E channels under the same circumstances. HEK293 cells normally contained G-proteins from all of the four major families. Inhibition of Ca currents by kappa agonists in alpha1B-expressing cells was enhanced slightly by the cotransfection of several G-protein alpha subunits. kappa agonists, however, had no effect in alpha1E-containing cells, even after overexpression of different G-protein alpha-subunits. In summary, these results demonstrate that there is a large difference in the susceptibility of alpha1B- and alpha1E-based Ca channels to regulation by G-proteins. This is so despite the fact that the two types of Ca channels show substantial similarities in their primary sequences.

Calcium Channels↗
PubMed1996

gp120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action of TGF-beta1.

We found that TGF-beta1, a cytokine that previously has been reported to have neuroprotective effects, was able to prevent the toxicity induced by the HIV-1 coat protein gp120 in hippocampal pyramidal neuron cultures. In the presence of glia, gp120 induced time- and dose-dependent cell death, which was more pronounced in mature (7-19 d in culture) than in young neurons (2-7 d in culture). Staining with nuclear dyes (propidium iodide and Hoechst 33342), in situ detection of DNA fragments, and DNA analysis on agarose gels indicated that apoptosis was mainly responsible for the death caused by the viral protein. However, after several days of treatment, death-displaying necrotic features also occurred. Neurotoxicity induced by gp120 was dependent on the activation of NMDA receptors and required the presence of glia as well as new protein synthesis. Thus, the effect of gp120 was abolished by the NMDA receptor antagonist APV and partially reduced by cycloheximide. Only modest neurotoxicity was observed in pure neuronal cultures deprived of the glia feeder layer. Fura-2-based videoimaging showed that treatment with gp120 enhanced the ability of NMDA to increase neuronal [Ca2+]i. The impairment of neuronal Ca2+ homeostasis was prevented completely by TGF-beta1. Therefore, it is likely that the neuroprotective action of the cytokine is attributable to its ability to stabilize neuronal [Ca2+]i.

Animals↗
PubMed1996

Percutaneous, transperineal cryosurgery of the prostate as salvage therapy for post radiation recurrence of adenocarcinoma.

BACKGROUND: Surgical techniques utilizing the application of very low temperatures to malignant tissues have been used increasingly in recent years in the minimally invasive treatment of prostate cancer. An area of potential application appears to be in the management of radiation resistant prostate cancer. METHODS: This study represents a retrospective chart review of 33 patients undergoing cryosurgical ablation of the prostate (CSAP) according to a protocol designed by an institutional review board at a single institution for the treatment of radiation resistant prostate cancer. Radiation resistance was defined as a positive prostate needle biopsy and rising prostate specific antigen (PSA). Treatment effect was assessed by serial post treatment PSA determinations and extensive systematic post treatment prostate needle biopsies. RESULTS: Of the 33 patients analyzed, 24 converted to an all negative biopsy status after one CSAP treatment. Repeat treatment converted two additional patients to a biopsy negative status. CSAP appeared to lower PSA dramatically in most patients. One year after treatment, of 10 patients not on androgen deprivation therapy, 3 maintained a PSA of < 0.4 ng/mL and those patients with androgen deprivation therapy maintained a PSA of < 4.0 ng/mL. The most frequent complications included sloughing syndrome (15.4%) and incontinence (10.3%). CONCLUSIONS: CSAP appears to eliminate biopsy detectable prostate tumor effectively in the majority of cases in the salvage setting following radiation therapy. A significant discrepancy exists, however, between the biopsy "cure" rate and the biochemical "cure" rate, even in the short term. There is a suggestion that early detection of radiation failure may improve results of this salvage therapy.

Adenocarcinoma↗
PubMed1996

Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine.

Digital-imaging microfluorimetry of the oxidation of hydroethidine (HEt) to ethidium can be used to monitor superoxide (O2-) production selectively within individual rat hippocampal pyramidal neurons in culture and in brain slices. Under assay conditions, oxidation was not accomplished by hydroxyl radical, singlet O2, H2O2, or nitrogen radicals. Neuronal O2- production varied with metabolic activity and age. O2- generation increased after treatment with AMPA, kainic acid, and NMDA, and the mitochondrial uncoupler carbonylcyanide p-(trifluoromethoxy)phenyl hydrazone, but usually not after depolarization (50 mM K+). O2- concentrations were sensitive to scavengers and nitric oxide. HEt oxidation was higher in Ca(2+)-containing versus Ca(2+)-free saline. However, Ca2+ ionophores did not increase oxidation greatly. H2O2 application produced a secondary increase in O2-. The major source of O2- under basal and stimulated conditions appeared to be the mitochondria. Consistent with this, ethidium staining in dendrites was punctate, colocalized with mitochondria, and blocked by CN-.

Animals↗
PubMed1996

Regulatory differences in the stress response of hippocampal neurons and glial cells after heat shock.

During periods of stress, cells depend on a transient, highly conserved, and regulated response to maintain homeostasis. This "heat shock response" is mediated transcriptionally by a multigene family of heat shock factors (HSF). The presence of multiple HSF suggests that activation of a given HSF is stress-specific. Using Western blot analysis, we have demonstrated the inability of primary cultured rat hippocampal neurons to induce a heat shock response after hyperthermia. In contrast, secondary cultured rat glial cells demonstrated a robust response. Examination of whole-cell extracts from the two cell types with gel shift mobility analysis and Western blot analysis revealed that although glial cells express HSF1 and HSF2, hippocampal neurons only express HSF2. Incubation of whole-cell extracts with monoclonal antisera raised against HSF1 and HSF2 before gel shift mobility analysis demonstrated HSF1 DNA-binding activity in glial cells and HSF2 DNA-binding activity in neurons. HSF1 has been shown to be the principal mediator of heat-induced heat shock gene expression. These results suggest that the deficient heat shock response of hippocampal neurons at this developmental stage is attributable to a lack of HSF1 expression. Furthermore, these results suggest that considerations of selective neuronal vulnerability to environmental stress should include the principal mediators of the stress response, the HSF.

Animals↗
PubMed1996

Developmental regulation of the toxin sensitivity of Ca(2+)-permeable AMPA receptors in cortical glia.

We examined the properties of glutamate agonist-induced Ca2+ fluxes in cultured CG-4 and O-2A progenitor cells from rat cortex. Kainate-induced Ca2+ fluxes in these cells were found to be attributable to the activation of AMPA receptors. Thus, these fluxes were enhanced by cyclothiazide but not by concanavalin A and were blocked completely by GYKI-53655. We simultaneously examined kainate-induced Ca2+ entry and Na+ currents in these cells under voltage-clamp conditions. Both of these parameters were blocked by Joro spider toxin (JSTx) in undifferentiated cells. However, neither JSTx nor Argiotoxin 636 effectively blocked either parameter in cells differentiated into type II astrocytes. This change in toxin sensitivity occurred slowly over a period of several days. Similar results were obtained in Ca(2+)-imaging studies. When cells were differentiated into oligodendrocytes, they showed an intermediate sensitivity to block by JSTx as assessed using imaging and voltage-clamp studies. Analysis of the expression of AMPA-receptor subunits showed an increase in the concentration of glutamate receptor-2 (GluR2) in CG-4 cells as they differentiated into type II astrocytes and oligodendrocytes. These results demonstrate that the AMPA receptors in cells of the O-2A lineage flux appreciable amounts of Ca2+ but may contain variable amounts of edited GluR2 subunits.

Animals↗
PubMed1996

Sphingosine and sphingosine 1-phosphate differentially modulate platelet-derived growth factor-BB-induced Ca2+ signaling in transformed oligodendrocytes.

The roles of sphingosine and sphingosine 1-phosphate in Ca2+ signaling following platelet-derived growth factor (PDGF) receptor stimulation were investigated in the oligodendrocyte cell line CEINGE cl3, using single-cell fura-2 microfluorimetry and videoimaging. Two different Ca2+ responses were observed, which differed in their delays and kinetics. The first response, which occurred after a shorter delay, exhibited a single Ca2+ peak often followed by a plateau, while the second type of response was characterized by a longer delay and by Ca2+ spikes with different frequencies and amplitudes. The latter phenomenon was never observed after stimulation of G protein-coupled receptors for ATP, ET-1, and BK. The incubation with the inhibitor of sphingosine kinase, DL-threo-dihydrosphingosine, significantly increased the percentage of cells responding to PDGF-BB exposure with Ca2+ spikes (87 versus 47%), while it did not modify the Ca2+ response elicited by exposure to ATP, ET-1, or BK. Exposure to exogenous 10 microM sphingosine or 1 microM sphingosine 1-phosphate produced oscillatory and non-oscillatory Ca2+ responses, respectively, similar to those elicited by PDGF-BB. A second application of PDGF-BB, 30 min after the first, was normally ineffective in producing a Ca2+ response. However, if the second exposure was preceded by the inhibition of sphingosine 1-phosphate formation, an oscillatory Ca2+ response occurred in all cells. We conclude that intracellular levels of sphingosine and sphingosine 1-phosphate may differentially modulate Ca2+ signaling triggered by PDGF receptor stimulation in CEINGE cl3-transformed oligodendrocytes.

Becaplermin↗
PubMed1996

Opposite effects of TGF-beta 1 on rapidly- and slowly-triggered excitotoxic injury.

Transforming growth factor-beta (TGF-beta) has been shown to protect central neurons against diverse metabolic and excitotoxic challenges. We induced different types of excitotoxic injury on cultured rat hippocampal neurons and investigated TGF-beta 1 for its protective activity. TGF-beta 1 (0.3-10 ng/ml) effectively blocked excitotoxic injury of cultured rat hippocampal neurons induced by short-term exposure to the selective agonist N-methyl-D-aspartate (NMDA; 100 microM, 20 min). Excitotoxic injury caused by long-term exposure to the non-NMDA agonists kainate (50 microM, 24 hr) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 10 microM, 24 hr) caused a similar reduction in neuronal viability. However, treatments with TGF-beta 1 (0.1-10 ng/ml) actually potentiated this slowly-triggered excitotoxic injury. Cultures of rat cerebellar neurons enriched for Purkinje cells have been shown to express AMPA/kainate receptors with significant permeability to Ca2+ and to be uniquely sensitive to non-NMDA receptor-mediated neurotoxicity. In this culture system, short-term exposure to kainate (100 microM; 30 min) in Na(+)-free extracellular solution caused a pronounced decrease in neuronal viability, and this toxicity was also significantly reduced in cultures treated with TGF-beta 1 (10 ng/ml). These results suggest that TGF-beta 1 has the capacity to protect neurons against rapidly-triggered, Ca(2+)-mediated excitotoxic injury, but significantly potentiates slowly-triggered types of excitotoxic injury. This complex action of TGF-beta 1 could have important implications for the use of TGF-beta s and related growth factors in the treatment of neurodegenerative diseases.

Animals↗
PubMed1996

Cryosurgical ablation of the prostate: two-year prostate-specific antigen and biopsy results.

OBJECTIVES: Percutaneous cryosurgical ablation of the prostate (CSAP) was performed on patients with localized or locally advanced adenocarcinoma of the prostate. To assess local disease control, post-treatment biopsy and serum prostate-specific antigen (PSA) levels were obtained at 3 and 24 months post-treatment. METHODS: From June 1990 through May 1994, CSAP was performed 448 times on 383 patients under Institutional Review Board protocols. A urethral warming catheter was used for all procedures. A total of 239 patients were followed for a minimum of 21 months after treatment. None of this group had received prior local treatment. The group consisted of patients who were newly diagnosed and treated solely with cryotherapy (virgin); the remainder had been on androgen deprivation therapy (ADT) prior to CSAP. RESULTS: Biopsies were obtained from 114 patients at 21 months or more after treatment. In the virgin group, 79% had a negative biopsy after one or more treatments, and 88% of the ADT group are negative after one or more treatments. Overall, 69% had a negative biopsy after one treatment and 82% had a negative biopsy following one or more CSAP treatments. Of a group of 163 patients, PSA data were evaluable at 21 months or more after treatment. In the virgin group, 60% had a PSA 0.4 ng/mL or less, and 77% had a PSA 1.0 ng/mL or less. In the ADT group, 40% had a PSA 0.4 ng/mL or less, and 69% had a PSA value of 1.0 ng/m Lor less. Complications were minimal, the most common one being urethral tissue sloughing, which occurred in 10% of patients. CONCLUSIONS: CSAP appears to be effective in obtaining local control as measured by biopsy and PSA 21 months or more post-treatment. When retrospectively comparing our results with recently published radiotherapy series, CSAP was more effective in obtaining nadir PSA values 1.0 ng/mL or less and negative biopsies at 21 months or more after treatment.

Adenocarcinoma↗
PubMed1996

Mechanism of inhibition of calcium channels in rat nucleus tractus solitarius by neurotransmitters.

1. High-threshold Ca2+ channel currents were measured every 15 s following a 200 ms voltage step from -80 mV to 0 mV in order to study the coupling mechanism between neurotransmitter receptors and Ca2+ channels in neurones acutely isolated from the nucleus tractus solitarius (NTS) of the rat. 2. Application of 30 microM baclofen (GABAB receptor agonist) caused 38.9 +/- 1.2% inhibition of the peak inward Ba2+ current (IBa2+) in most NTS cells tested (n = 85 of 88). Somatostatin, 300 nM, also reduced IBa2+ by 31.3 +/- 1.6% in 53 cells of 82 tested. 3. Activation of mu-opioid-, GABAB- or somatostatin-receptors inhibited both N- and P/Q-type Ca2+ channels. 4. The inhibition of Ca2+ currents by DAMGo (mu-opioid receptor agonist), baclofen and somatostatin was reduced by treatment with pertussis toxin and partially relieved by application of a 50 ms conditioning prepulse to +80 mV. This suggests that a pertussis toxin-sensitive G-protein was involved in the neurotransmitter-mediated action in the observed inhibition of Ca2+ currents. 5. Intracellular loading with an antiserum raised against the amino terminus of Go alpha (GC/2) markedly attenuated the somatostatin-induced inhibition, but did not block the DAMGO- and baclofen-induced inhibition. 6. These findings suggest at least two different pertussis toxin-sensitive G-protein-mediated pathways are involved in receptor-induced inhibition of Ca2+ currents in the NTS.

Animals↗
PubMed1996

Lesions of the triangular fibrocartilage complex: MR findings with a three-dimensional gradient-recalled-echo sequence.

PURPOSE: To evaluate the use of a three-dimensional gradient-recalled-echo (GRE) magnetic resonance (MR) imaging sequence in the depiction of lesions of the triangular fibrocartilage (TFC) complex. MATERIALS AND METHODS: MR images of the TFC complex were evaluated in 31 patients who underwent wrist arthroscopy less than 6 months after MR imaging. The results were compared with the arthroscopic findings. RESULTS: Eleven of 12 full-thickness TFC tears were depicted, but one partial-thickness tear, one abnormal disk, and one normal disk were overstaged. Lesions in the volar and dorsal radioulnar ligament and lesions of the attachments of the TFC complex to the ulna often were overstaged. Lesions of the ulnolunate and ulnotriquetral ligaments often were understaged. CONCLUSION: Imaging with the three-dimensional GRE sequence is reliable in the depiction of TFC tears and the exclusion of tears of components of the TFC complex other than those of the ulnolunate and ulnotriquetral ligaments.

Adult↗
PubMed1996

Scapholunate ligament: normal MR appearance on three-dimensional gradient-recalled-echo images.

PURPOSE: To evaluate the (a) capability of coronal three-dimensional (3D) gradient-recalled-echo (GRE) images in the demonstration of the volar, middle, and dorsal portions of the scapholunate ligament (SLL); (b) normal magnetic resonance (MR) appearance of these portions and of their attachment to the lunate and scaphoid; and (c) normal appearance of the ligament-cartilage interface for various portions of the SLL. MATERIALS AND METHODS: Coronal 3D GRE imaging was used to study the volar, middle, and dorsal portions of the SLL in 14 patients with an arthroscopically normal SLL and in five cadaveric wrists that had a normal SLL proved with dissection. RESULTS: The trapezoidal volar portion of the SLL was seen with inhomogeneous high intermediate signal intensity and attached directly to the lunate and scaphoid cortex. The triangular middle portion was seen with inhomogeneous intermediate signal intensity and in most cases attached to the hyaline cartilage of the lunate and scaphoid. The low-signal-intensity bandlike dorsal portion attached either to the cartilage, cartilage and cortex, or cortex alone of the lunate and scaphoid. CONCLUSION: The volar, middle, and dorsal portions of the SLL can be differentiated on the basis of MR appearance on 3D GRE images. The various portions attach to cartilage and/or to cortex, and the appearance of the ligament-cartilage interface follows a specific pattern.

Adolescent↗
PubMed1996

Presynaptic inhibition at excitatory hippocampal synapses: development and role of presynaptic Ca2+ channels.

1. Presynaptic inhibition of excitatory postsynaptic currents (EPSCs) induced by activation of adenosine receptors was examined at hippocampal synapses in cell culture. Changes in the degree of presynaptic inhibition during development were examined. The results were then used to test the role of presynaptic Ca2+ channels in presynaptic inhibition. 2. Application of the selective A1 adenosine receptor agonist N6-cyclopentyladenosine (CPA) reduced EPSCs measured with the use of whole cell voltage-clamp procedures. In cells grown in culture for < 15 days, CPA (100 nM) inhibited EPSCs by 74 +/- 2%. In cells grown in culture for > 20 days, the same concentration of CPA inhibited EPSCs by 47 +/- 3%. 3. In mature cells (grown in culture for > 20 days), application of the selective N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CTx GVIA; 2.5 microM) partially occluded the effects of CPA. In contrast, the P/Q channel blocker omega-Aga IVA enhanced the effects of CPA. Both toxins reduced the amplitude of the EPSC. 4. omega-CTx GVIA was applied to the EPSC that remained after application of 100 nM CPA. Under these conditions, omega-CTx GVIA reduced the EPSC by less than when omega-CTx GVIA was applied under control conditions. In contrast, when omega-Aga IVA was applied in the presence of CPA, the toxin reduced the EPSC to a greater extent than when it was applied under control conditions. 5. Somatic Ca(2+)-channel currents were inhibited by CPA. This effect was partially occluded by pretreatment with omega-CTx GVIA but was unaffected by pretreatment with omega-Aga IVA (1 microM). Both toxins blocked part of the somatic Ca(2+)-channel current. 6. The results indicate that inhibition of presynaptic N-type Ca2+ channels accounted for 40-50% of presynaptic inhibition, another type of Ca2+ channel may participate as well. In addition, the efficacy of presynaptic inhibition declined during synapse maturation due in part to a developmental decline in the relative contribution of N-type channels to transmitter release.

Adenosine↗
PubMed1996

Protective effect of transforming growth factor-beta 1 on beta-amyloid neurotoxicity in rat hippocampal neurons.

Neurodegeneration associated with Alzheimer's disease is believed to involve toxicity to beta-amyloid (A beta) and related peptides. Treatment of cultured rat hippocampal neurons with A beta 1-40 (1 microM) or the active fragment A beta 25-35 (1 microM) for 5 days led to a approximately 40-50% decrease in neuronal viability. The hydrophilic antioxidant ascorbic acid (300 microM) and the lipophilic antioxidant 2-mercaptoethanol (10 microM) both protected significantly against A beta neurotoxicity. Despite the protective effects of these antioxidants, both acute and chronic treatments with A beta 25-35 did not increase production of superoxide anions, as monitored with the fluorescent probe hydroethidine. Similarly, overexpression of Cu/Zn-superoxide dismutase using adenovirus-mediated gene transfer did not protect against A beta neurotoxicity. A beta neurotoxicity, however, was prevented in cultures infected with a recombinant, replication-defective adenovirus overexpressing the Ca2+ binding protein calbindin D28k. Transforming growth factor-beta 1 (TGF-beta 1) has been shown to protect neurons against both Ca(2+)- and free radical-mediated neuronal degeneration. We found that A beta neurotoxicity was significantly attenuated by single treatments with TGF-beta 1 (0.1-10 ng/ml) and prevented by repetitive treatments (10 ng/ml/day). The protective effects of TGF-beta 1 were associated with a preservation of mitochondrial potential and function, as determined with rhodamine-123-based microfluorimetry. Because both increased oxidative stress and pathophysiological Ca2+ fluxes can impair mitochondrial function, preservation of mitochondrial potential by TGF-beta 1 could be directly associated with its protection against A beta neurotoxicity. The ability of TGF-beta 1 to increase the expression of the anti-apoptotic proteins Bcl-2 and Bcl-XL is discussed in this context.

6-Cyano-7-nitroquinoxaline-2,3-dione↗