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Berlin Brandenburg

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  • 1
    Language: English
    In: Brain Research, 2001, Vol.898(1), pp.27-35
    Description: ( R )-Apomorphine is a non-selective dopamine (DA) agonist which is used in the treatment of Parkinson’s disease. In addition to symptomatic effects, apomorphine exerts a neuroprotective activity in specific experimental models. For instance, apomorphine prevents experimental parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroprotection obtained with apomorphine does not seem to be related to its dopamine (DA) agonist properties, instead it appears to be grounded on the antioxidant and the free radical scavenging effects of the compound. In this study, we sought to determine whether apomorphine protects against methamphetamine toxicity. We found that apomorphine (1; 5 and 10 mg/kg) dose-dependently protects against methamphetamine- (5 mg/kg X3, 2 h apart) induced striatal DA loss and reduction of tyrosine hydroxylase (TH) activity in the rat striatum. These protective effects are neither due to a decrease in the amount of striatal methamphetamine nor to hypothermia as indicated by measurement of striatal methamphetamine and body temperature at different time intervals after drug administration. The effects of apomorphine were neither opposite to, nor reversed by the DA antagonist haloperidol despite no decrease in body temperature was observed when apomorphine was given in combination with haloperidol. The present data are in line with recent studies suggesting a DA receptor-independent neuroprotective effect of apomorphine on DA neurons and call for further studies aimed at evaluating potential neuroprotective effects of apomorphine in Parkinson’s disease.
    Keywords: Apomorphine ; Body Temperature ; Haloperidol ; Methamphetamine ; Neurodegeneration ; Neuroprotection ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 2
    Language: English
    In: Brain Research, 2009, Vol.1265, pp.75-79
    Description: A 7-day treatment with memantine (25 mg/kg, i.p.), a drug that is currently prescribed for the treatment of Alzheimer's disease, increased the levels of brain-derived neurotrophic factor (BDNF) and reduced the expression of the neuron-specific K /Cl co-transporter, KCC2, in the hippocampus and cerebral cortex of mice. Knowing that KCC2 maintains low intracellular Cl concentrations, which drive Cl influx in response to GABA receptor activation, we monitored the behavioural response to the GABA receptor enhancer, diazepam, in mice pre-treated for 7 days with saline or 25 mg/kg of memantine. Memantine treatment substantially attenuated motor impairment induced by an acute challenge with diazepam (6 mg/kg, i.p.), as assessed by the rotarod test and the horizontal wire test. We suggest that a prolonged treatment with memantine induces changes in the activity of GABA receptors that might contribute to the therapeutic and/or toxic effects of the drug.
    Keywords: Memantine ; Kcc2 ; Bdnf ; Gaba A Receptor ; Diazepam ; Rotarod Test ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 3
    Language: English
    In: Brain research, 11 June 2007, Vol.1153, pp.58-67
    Description: Transient focal ischemia produced by local infusion of endothelin-1 (ET1) in the territory of the middle cerebral artery has been proposed as a potentially useful model for the screening of drugs developed for the treatment of thrombo-embolic stroke. However, most of the data rely exclusively on the assessment of the infarct volume, which is only a partial predictor of the neurological outcome of stroke. Here, we have validated the model using a multimodal approach for the assessment of neuroprotection, which includes (i) determination of the infarct volume by 2,3,5-triphenyltetrazolium chloride staining; (ii) an in-depth behavioral analysis of the neurological deficit; and (iii) an EEG analysis of electrophysiological abnormalities in the peri-infarct somatosensory forelimb cortical area, S1FL. The non-competitive NMDA receptor antagonist, MK-801 (3 mg/kg, injected i.p. 20 min after ET1 infusion in conscious rats) could reduce the infarct volume, reverse the EEG changes occurring at early times post-ET1, and markedly improve the neurological deficit in ischemic animals. The latter effect, however, was visible at day 3 post-ET1, because the drug itself produced substantial behavioral abnormalities at earlier times. We conclude that a multimodal approach can be applied to the ET1 model of focal ischemia, and that MK-801 can be used as a reference compound to which the activity of safer neuroprotective drugs should be compared.
    Keywords: Endothelin-1 ; Dizocilpine Maleate -- Therapeutic Use ; Ischemic Attack, Transient -- Chemically Induced ; Neuroprotective Agents -- Therapeutic Use
    ISSN: 0006-8993
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 4
    Language: English
    In: Brain Research, 2007, Vol.1165, pp.21-29
    Description: The use of anabolic–androgenic steroids (AASs) in the world of sport has raised a major concern for the serious, sometimes life-threatening, side effects associated with these drugs. Most of the CNS effects are of psychiatric origin, and whether or not AASs are toxic to neurons is yet unknown. We compared the effect of testosterone with that of the AASs, 19-nortestosterone (nandrolone), stanozolol, and gestrinone, on excitotoxic neuronal death induced by -methyl- -aspartate (NMDA) in primary cultures of mouse cortical cells. In the most relevant experiments, steroids were applied to the cultures once daily during the 4 days preceding the NMDA pulse. Under these conditions, testosterone amplified excitotoxic neuronal death only at very high concentrations (10 μM), whereas it was protective at concentrations of 10 nM and inactive at intermediate concentrations. Low concentrations of testosterone became neurotoxic in the presence of the aromatase inhibitors, i.e. anastrozole and aminoglutethimide, suggesting that the intrinsic toxicity of testosterone was counterbalanced by its aromatization into 17β-estradiol. As opposed to testosterone, nortestosterone, stanozolol and gestrinone amplified NMDA toxicity at nanomolar concentrations; their action was insensitive to aromatase inhibitors, but was abrogated by the androgen receptor antagonist, flutamide. None of the AASs were toxic in the absence of NMDA. These data suggest that AASs increase neuronal vulnerability to an excitotoxic insult and may therefore facilitate neuronal death associated with acute or chronic CNS disorders.
    Keywords: Excitotoxicity ; Androgen ; Estrogen ; Cortifical Culture ; Anabolic Steroid ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 5
    Language: English
    In: Brain research, 24 August 2007, Vol.1165, pp.21-9
    Description: The use of anabolic-androgenic steroids (AASs) in the world of sport has raised a major concern for the serious, sometimes life-threatening, side effects associated with these drugs. Most of the CNS effects are of psychiatric origin, and whether or not AASs are toxic to neurons is yet unknown. We compared the effect of testosterone with that of the AASs, 19-nortestosterone (nandrolone), stanozolol, and gestrinone, on excitotoxic neuronal death induced by N-methyl-d-aspartate (NMDA) in primary cultures of mouse cortical cells. In the most relevant experiments, steroids were applied to the cultures once daily during the 4 days preceding the NMDA pulse. Under these conditions, testosterone amplified excitotoxic neuronal death only at very high concentrations (10 muM), whereas it was protective at concentrations of 10 nM and inactive at intermediate concentrations. Low concentrations of testosterone became neurotoxic in the presence of the aromatase inhibitors, i.e. anastrozole and aminoglutethimide, suggesting that the intrinsic toxicity of testosterone was counterbalanced by its aromatization into 17beta-estradiol. As opposed to testosterone, nortestosterone, stanozolol and gestrinone amplified NMDA toxicity at nanomolar concentrations; their action was insensitive to aromatase inhibitors, but was abrogated by the androgen receptor antagonist, flutamide. None of the AASs were toxic in the absence of NMDA. These data suggest that AASs increase neuronal vulnerability to an excitotoxic insult and may therefore facilitate neuronal death associated with acute or chronic CNS disorders.
    Keywords: Androgens -- Pharmacology ; Excitatory Amino Acid Agonists -- Toxicity ; N-Methylaspartate -- Toxicity ; Neuroglia -- Physiology ; Neurons -- Drug Effects ; Testosterone -- Pharmacology
    ISSN: 0006-8993
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    Language: English
    In: Brain Research, 2007, Vol.1153, pp.58-67
    Description: Transient focal ischemia produced by local infusion of endothelin-1 (ET1) in the territory of the middle cerebral artery has been proposed as a potentially useful model for the screening of drugs developed for the treatment of thrombo-embolic stroke. However, most of the data rely exclusively on the assessment of the infarct volume, which is only a partial predictor of the neurological outcome of stroke. Here, we have validated the model using a multimodal approach for the assessment of neuroprotection, which includes (i) determination of the infarct volume by 2,3,5-triphenyltetrazolium chloride staining; (ii) an in-depth behavioral analysis of the neurological deficit; and (iii) an EEG analysis of electrophysiological abnormalities in the peri-infarct somatosensory forelimb cortical area, S1FL. The non-competitive NMDA receptor antagonist, MK-801 (3 mg/kg, injected i.p. 20 min after ET1 infusion in conscious rats) could reduce the infarct volume, reverse the EEG changes occurring at early times post-ET1, and markedly improve the neurological deficit in ischemic animals. The latter effect, however, was visible at day 3 post-ET1, because the drug itself produced substantial behavioral abnormalities at earlier times. We conclude that a multimodal approach can be applied to the ET1 model of focal ischemia, and that MK-801 can be used as a reference compound to which the activity of safer neuroprotective drugs should be compared.
    Keywords: Endothelin-1 Model of Ischemia ; Mk-801 ; Electrophysiological Outcome ; Neurological Deficit ; Neuroprotection ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 7
    Language: English
    In: Brain Research, 1985, Vol.332(1), pp.179-183
    Description: Repeated doses of estradiol benzoate (10 μg/kg, s.c., once a day for 2, 5 or 8 days) to male rats decreased γ-aminobutyric acid (GABA) content and glutamate decarboxylase (GAD) activity in substantia nigra (SN) but failed to change these parameters in hippocampus, cerebral cortex, cerebellum, lateral septum and olfactory tubercle. In the caudate nucleus, estradiol benzoate decreased GABA concentration but did not modify GAD activity. A decrease in nigral GABA concentration and GAD activity was also observed 24 and 48 but not 3 h after a single injection of estradiol benzoate. These data are consistent with results on GAD activity reported by McGinnis et al. in ovariectomized rats. Kinetic analysis of nigral GAD activity revealed that repeated estradiol benzoate injection reduced the V without affecting the of GAD. Estradiol benzoate also reduced the rate of nigral GABA accumulation resulting from local infusion of gabaculine, suggesting that the steroid decreases GABA turnover in male rat SN. Hypophysectomy decreased GABA content and GAD activity in SN and GABA content in striatum. Administration of estradiol benzoate for 8 days to hypophysectomized rats failed to decrease further these parameters. Taken together, these data suggest that estradiol benzoate decreases SN GABAergic activity and that the integrity of the pituitary gland is required for this effect.
    Keywords: Estradiol Benzoate ; Substantia Nigra ; Γ-Aminobutyric Acid (Gaba) Activity ; Glutamate Decarboxylase (Gad) Activity ; Gabaculine ; Hypophysectomy ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 8
    Language: English
    In: Brain Research, 1991, Vol.555(1), pp.65-69
    Description: The influence of estrogen on stimulation of inositol phospholipid hydrolysis by norepinephrine and carbamylcholine has been studied by measuring the accumulation of [ H]inositolmonophosphate ([ H]InsP) in cortical, hippocampal and striatal slices from ovariectomized rats. Repeated (but not a single) subcutaneous injections of estradiol benzoate (EB) (2 μg/animal once every 2 days for 10 days) markedly reduced stimulation of inositol phospholipid hydrolysis by norepinephrine in hippocampus and corpus striatum. Conversely, the efficacy of norepinephrine was increased in cortical slices. Estrogen treatment did not affect basal or carbamylcholine-stimulated [ H]InsP formation. In vitro addition of 17β-estradiol (1–100 nM) failed to modify norepinephrine- or carbamylcholine-induced [ H]InsP production in all regions examined. An increased density of -adrenergic binding sites in cortical membranes paralleled the enhanced responsiveness of inositol phospholipid hydrolysis to norepinephrine induced by EB treatment in this area, whereas no significant changes in [ H]prazosin binding were found in membranes from hippocampus and corpus striatum. These results indicate that estrogen may affect inositol phospholipid hydrolysis in discrete brain areas, suggesting a complex role for estradiol in modulating noradrenergic receptor activity in the central nervous system.
    Keywords: Estradiol Benzoate ; Norepinephrine ; Inositol Phospholipid Hydrolysis ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 9
    Language: English
    In: Brain Research, 2005, Vol.1047(1), pp.30-37
    Description: Nicergoline, a drug used for the treatment of Alzheimer's disease and other types of dementia, was tested for its ability to protect neurons against β-amyloid toxicity. Pure cultures of rat cortical neurons were challenged with a toxic fragment of β-amyloid peptide (βAP ) and toxicity was assessed after 24 h. Micromolar concentrations of nicergoline or its metabolite, MDL, attenuated βAP -induced neuronal death, whereas MMDL (another metabolite of nicergoline), the α -adrenergic receptor antagonist, prazosin, or the serotonin 5HT-2 receptor antagonist, methysergide, were inactive. Nicergoline increased the basal levels of Bcl-2 and reduced the increase in Bax levels induced by β-amyloid, indicating that the drug inhibits the execution of an apoptotic program in cortical neurons. In mixed cultures of rat cortical cells containing both neurons and astrocytes, nicergoline and MDL were more efficacious than in pure neuronal cultures in reducing β-amyloid neurotoxicity. Experiments carried out in pure cultures of astrocytes showed that a component of neuroprotection was mediated by a mechanism of glial–neuronal interaction. The conditioned medium of cultured astrocytes treated with nicergoline or MDL for 72–96 h (collected 24 h after drug withdrawal) was neuroprotective when transferred to pure neuronal cultures challenged with β-amyloid. In cultured astrocytes, nicergoline increased the intracellular levels of transforming-growth factor-β and glial-derived neurotrophic factor, two trophic factors that are known to protect neurons against β-amyloid toxicity. These results raise the possibility that nicergoline reduces neurodegeneration in the Alzheimer's brain.
    Keywords: Β-Amyloid Toxicity ; Cortical Neurons ; Nicergoline ; Glial-Neuronal Interaction ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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  • 10
    Language: English
    In: Brain Research, 2005, Vol.1043(1), pp.95-106
    Description: Age-dependent changes in the expression of group I and II metabotropic glutamate (mGlu) receptors were studied by in situ hybridization, Western blot analysis and immunohistochemistry. Male Fisher 344 rats of three ages (3, 12 and 25 months) were tested. Age-related increases in mGlu1 receptor mRNA levels were found in several areas (thalamic nuclei, hippocampal CA3) with parallel increases in mGlu1a receptor protein expression. However, a slight decrease in mGlu1a receptor mRNA expression in individual Purkinje neurons and a decline in cerebellar mGlu1a receptor protein levels were detected in aged animals. In contrast, mGlu1b receptor mRNA levels increased in the cerebellar granule cell layer. Although mGlu5 receptor mRNA expression decreased in many regions, its protein expression remained unchanged during aging. Compared to the small changes in mGlu2 receptor mRNA levels, mGlu3 receptor mRNA levels showed substantial age differences. An increased mGlu2/3 receptor protein expression was found in the frontal cortex, thalamus, hippocampus and corpus callosum in aged animals. These results demonstrate region- and subtype-specific, including splice variant specific changes in the expression of mGlu receptors in the brain with increasing age.
    Keywords: Aging, Metabotropic Glutamate Receptors ; Rat Brain ; In Situ Hybridization ; Western Blot ; Immunohistochemistry ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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