Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT.
 ...
PMID:Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. 1220 Jan 98

Epidemiologic studies revealed that the prevalence of Parkinson disease is higher in males than in females and that the progression of the disease might be rapid in males compared with females. The reason for the gender difference is unknown; however, estrogens may be involved. Many studies have revealed that estrogens provide neuroprotective effects and that the protective mechanisms include antioxidant property and upregulation of Bcl-2, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor (GDNF). Upregulation of Bcl-2 or GDNF is mediated by nonnuclear estrogen receptor (ER) in addition to transcription regulation by ER. To avoid undesirable effect of estrogens, several selective ER modulators, raloxifene and genistein are considered.
 ...
PMID:Estrogens and Parkinson disease: novel approach for neuroprotection. 1277 6

In order to test the functional implication of herpes simplex virus (HSV) vector-mediated gene transfer after axonal injury, we injected replication-incompetent HSV vectors coding for the anti-apoptotic peptide Bcl-2 and the glial cell-derived neurotrophic factor (GDNF), separately or in combination into ventral spinal cord 30 min after a crush injury to the proximal spinal root that was combined with moderate mechanical traction. HSV-mediated expression of Bcl-2 or GDNF enhanced functional recovery assessed by histologic, electrophysiologic, and behavioral parameters up to 5 months after injury. The most sensitive measure of distal motor function, the sciatic function index, was significantly improved in animals injected with the two vectors together. These results suggest an approach to root trauma that might be used to enhance functional recovery after injury.
 ...
PMID:Enhanced functional recovery after proximal nerve root injury by vector-mediated gene transfer. 1476 80

Guanosine has many trophic effects in the CNS, including the stimulation of neurotrophic factor synthesis and release by astrocytes, which protect neurons against excitotoxic death. Therefore, we questioned whether guanosine protected astrocytes against apoptosis induced by staurosporine. We evaluated apoptosis in cultured rat brain astrocytes, following exposure (3 h) to 100 nM staurosporine by acridine orange staining or by oligonucleosome, or caspase-3 ELISA assays. Staurosporine promoted apoptosis rapidly, reaching its maximal effect (approximately 10-fold over basal apoptotic values) in 18-24 h after its administration to astrocytes. Guanosine, added to the culture medium for 4 h, starting from 1 h prior to staurosporine, reduced the proportion of apoptotic cells in a concentration-dependent manner. The IC50 value for the inhibitory effect of guanosine is 7.5 x 10(-5) M. The protective effect of guanosine was not affected by inhibiting the nucleoside transporters by propentophylline, or by the selective antagonists of the adenosine A1 or A2 receptors (DPCPX or DMPX), or by an antagonist of the P2X and P2Y purine receptors (suramin). In contrast, pretreatment of astrocytes with pertussis toxin, which uncouples Gi-proteins from their receptors, abolished the antiapoptotic effect of guanosine. The protective effect of guanosine was also reduced by pretreatment of astrocytes with inhibitors of the phosphoinositide 3-kinase (PI3K; LY294002, 30 microM) or the MAPK pathway (PD98059, 10 microM). Addition of guanosine caused a rapid phosphorylation of Akt/PKB, and glycogen synthase kinase-3beta (GSK-3beta) and induced an upregulation of Bcl-2 mRNA and protein expression. These data demonstrate that guanosine protects astrocytes against staurosporine-induced apoptosis by activating multiple pathways, and these are mediated by a Gi-protein-coupled putative guanosine receptor.
 ...
PMID:The antiapoptotic effect of guanosine is mediated by the activation of the PI 3-kinase/AKT/PKB pathway in cultured rat astrocytes. 1509 66

Pramipexole hydrochloride (pramipexole) is a nonergot dopamine D(2) agonist, and the S(-)enantiomer is used for the treatment of Parkinson's disease (PD). Pramipexole possessed the highest affinity with the D(3) subtype among the D(2) receptor subfamily members (D(2), D(3), D(4)), lacking affinity with the D(1) and D(5) subtype. Pramipexole ameliorated the motor disturbances in PD animal models, induced contralateral rotational behavior reflecting post-synaptic D(2) receptor stimulation in the striatum, and showed a variety of neuroprotective effects in vitro and in vivo experimental systems. The neuroprotective effects of pramipexole seemed to be derived from several mechanisms: stimulation of D(2) autoreceptor, stimulation of D(3) receptor, inhibition of oxidative reaction and following radical production, increase of Bcl-2 protein and inhibition of apoptotic cell death, and production of neurotrophic factor. Clinical efficacy of pramipexole both in monotherapy and combined use with L-DOPA were confirmed evaluating by UPDRS (Unified Parkinson's Disease Rating Scale) II (Activities of daily living) and III (Motor), in the results of clinical studies mainly performed in USA and European countries and partly in Japan. In addition, patients initially treated with pramipexole demonstrated reduction in problematic symptoms and in loss of striatal [(123)I]2beta-carboxymethoxy-3beta-(4-idodophenyl)tropan uptake, a marker of dopamine neuron degeneration, compared with those initially treated with L-DOPA.
 ...
PMID:[Pharmacological profiles and clinical effects of antiparkinsonian agent, pramipexole]. 1517 83

Morphological and functional changes have been repeatedly reported in the brain organization of depressed patients. The main modifications demonstrated by structural magnetic resonance imaging (MRI) are a reduction in the gray matter volume within the prefrontal cortex, the hippocampus, and the striatum. The reduction in gray matter volume and the morphological atrophy are probably due to an excess of neural loss (apoptosis) and an altered regulation of the neurotrophic processes. Hence, a deficit in neurotrophic factor synthesis (brain-derived neurotrophic factor [BDNF], neurotrophin [NT]-3, NT-4/5, Bcl-2, etc.) may be responsible for increased apoptosis in the hippocampus and prefrontal cortex corresponding to the cognitive impairment described in depression. This hypothesis seems to be confirmed by the decreased expression of neurotrophic factors (e.g., BDNF mRNA) in animal models of depression. In parallel, the neural plasticity (functional aspects of synaptic connectivity and long-term potential activity [LTP]) is decreased. However, the most interesting data concern the possible reversibility of this dysregulation with antidepressant treatment. For example, communication between the hippocampus and the prefrontal cortex could be re-established, enabling in a way the cognitive processes to be "reset." From a clinical point of view, the consequences of such a phenomenon are manifold:
 ...
PMID:Neuroplasticity: from MRI to depressive symptoms. 1555 Mar 49

Nutrient deprivation during ischemia leads to severe insult to neurons causing widespread excitotoxic damage in specific brain regions such as the hippocampus. One possible strategy for preventing neurodegeneration is to express therapeutic proteins in the brain to protect against excitotoxicity. We investigated the utility of equine infectious anemia virus (EIAV)-based vectors as genetic tools for delivery of therapeutic proteins in an in vivo excitotoxicity model. The efficacy of these vectors at preventing cellular loss in target brain areas following excitotoxic insult was also assessed. EIAV vectors generated to overexpress the human antiapoptotic Bcl-2 or growth factor glial-derived neurotrophic factor (GDNF) genes protected against glutamate-induced toxicity in cultured hippocampal neurons. In an in vivo excitotoxicity model, adult Wistar rats received a unilateral dose of the glutamate receptor agonist N-methyl-D-aspartate to the hippocampus that induced a large lesion in the CA1 region. Neuronal loss could not be protected by prior transduction of a control vector expressing beta-galactosidase. In contrast, EIAV-mediated expression of Bcl-2 and GDNF significantly reduced lesion size thus protecting the hippocampus from excitotoxic damage. These results demonstrate that EIAV vectors can be effectively used to deliver putative neuroprotective genes to target brain areas and prevent cellular loss in the event of a neurological insult. Therefore these lentiviral vectors provide potential therapeutic tools for use in cases of acute neurotrauma such as cerebral ischemia.
 ...
PMID:Lentiviral-mediated delivery of Bcl-2 or GDNF protects against excitotoxicity in the rat hippocampus. 1558 9

The Bcl-2 family of apoptotic-regulating proteins plays important roles during both neural development and maintenance of tissue homeostasis. The major antiapoptotic family members, Bcl-x(L) and Bcl-2, and the major proapoptotic proteins, Bax and Bak, show distinct temporal and spatial patterns of expression in the developing brain. Targeted deletions of Bcl-x(L) and Bcl-2 as well as Bax and Bak have proven to be important tools in delineating the process of cell death in the nervous system. These genetic models show that Bcl-x(L) and Bax play crucial roles in regulating the survival of differentiating neurons. In contrast, Bax and Bak play redundant roles in regulating the size of the neural progenitor cell population in postnatal mice and in the normal development of the retinal layers of the eye. Bax, Bcl-x(L), and Bcl-2 regulate the apoptotic response to neurotrophic factor deprivation. In contrast, excitotoxic cell death is not dependent on either Bax or Bak. In fact, the absence of proapoptotic Bcl-2 proteins can enhance the toxicity of neuroexcitatory molecules. Together, these data establish the intrinsic apoptotic pathway regulated by Bcl-2 proteins as a critical but not exclusive regulator of neural cell survival.
 ...
PMID:Defining the role of the Bcl-2 family of proteins in the nervous system. 1563 74

In the present paper, we overview the discovery of new biological activities induced by ginsenoside Rg1 and Rb1 and discuss possible mechanisms of action. Both compounds could increase neural plasticity in efficacy and structure; especially Rg1, as one small molecular drug, can increase proliferation and differentiation of neural progenitor cells in dentate gyrus of hippocampus of normal adult mice and global ischemia model in gerbils. This finding has great value for treatment of Alzheimer's disease and other neurodegenerative disorders which is characterized by neurons loss. Increase of expression of brain derived neurotrophic factor, Bcl-2 and antioxidant enzyme, enhanced new synapse formation, inhibition of apoptosis and calcium overload are also important neuron protective factors. Rg1 and Rb1 have common effects, but there are some differences in pharmacology and mechanism. These differences may attribute to their different chemical structure. Rg1 is panaxtriol with two sugars, while Rb1 is panaxtriol with four sugars.
 ...
PMID:Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. 1566 89

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 beta-amyloid toxicity. Pure cultures of rat cortical neurons were challenged with a toxic fragment of beta-amyloid peptide (betaAP(25-35)) and toxicity was assessed after 24 h. Micromolar concentrations of nicergoline or its metabolite, MDL, attenuated betaAP(25-35)-induced neuronal death, whereas MMDL (another metabolite of nicergoline), the alpha1-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 beta-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 beta-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 beta-amyloid. In cultured astrocytes, nicergoline increased the intracellular levels of transforming-growth factor-beta and glial-derived neurotrophic factor, two trophic factors that are known to protect neurons against beta-amyloid toxicity. These results raise the possibility that nicergoline reduces neurodegeneration in the Alzheimer's brain.
 ...
PMID:Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against beta-amyloid toxicity. 1588 40


<< Previous 1 2 3 4 5 6 7 8 Next >>