Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease (PD) is pathologically characterized by progressively loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies. In 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced PD mice models, the calpain- cyclin-dependent kinase 5 (Cdk5)-myocyte enhancer factor 2 (MEF2) signaling has been proven in governing dopaminergic neuronal death. Under MPTP insult, p35 is cleaved by calpain into p25, which binds to Cdk5 and exhibits hyperactivity of Cdk5/p25. Cdk5/p25 inactivates MEF2, a survivor factor, which is critical for DA neuronal death. In this study, neuroprotective effect of the Cdk5/p25 specific peptide, TFP5, was evaluated in sub-acute MPTP induced PD mouse model by intraperitoneal (i.p.) injection of MPTP for five consecutive days. The results indicated that the levels of p35 and p25, and p25/p35 ratio increased in the sub-acute MPTP mice. TFP5 broadly reached cortex neuron, hippocampus and SNpc areas after i.p. injections. Pretreatment with 45mg/kg/day TFP5, as well as 10mgkg/day Cdk5 inhibitor roscovitine, for three days significantly rescued DA neuronal loss up to 9.8% or 9.7% respectively compared to the saline treated group. Treatment of TFP5 and roscovitine reduced the levels of inactive form of MEF2 and cleaved caspase 3, thus protected apoptosis of DA neurons against MPTP insult. Our results propose that TFP5 might be a potential therapeutic candidate for PD.
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PMID:Cdk5/p25 specific inhibitory peptide TFP5 rescues the loss of dopaminergic neurons in a sub-acute MPTP induced PD mouse model. 2754 41

Sevoflurane has been reported to induce neurotoxicity and cognitive impairment in the developing brains. However, the underlying molecular mechanisms remain poorly understood. Recent studies have demonstrated aberrant cyclin-dependent kinase 5 (CDK5) activity is implicated in inhaled anesthetic-induced neurotoxicity. CDK5/CRMP2 signaling is involved in the cortical and hippocampal dendritic development. The aim of present study is to investigate whether the CDK5/CRMP2 pathway mediates sevoflurane-induced dendritic development abnormalities. Rat primary cortical neurons were treated with 4% sevoflurane for 6h, the CDK5 inhibitor roscovitine or the vehicle (0.3% DMSO) was administered 12h before sevoflurane or carrying gases exposure. Cortical neurons were harvested for further analysis 0h, 12h and 24h after exposure. Sevoflurane exposure for 6h did not reduce cell viability and slightly increased the expression of cleaved caspase-3. Sevoflurane induced abnormal CDK5 activation by increasing the expression of its activator p25 and promoted the phosphorylation of CRMP2 (Ser522). The increased phospho-CRMP2 (Ser522) was mainly distributed in the cytoplasm of cortical neurons. Sevoflurane significantly reduced the number of primary dendrites and the number of branching points; whereas it did not influence the total dendritic length. Suppression of CDK5 activation with roscovitine attenuated neuronal apoptosis, hyperphosphorylation of CRMP2 (Ser522) and dendritic development abnormalities induced by sevoflurane. Our results indicate that activation of the CDK5/CRMP2 pathway may mediate sevoflurane-induced dendritic development abnormalities in the cortical neurons. The physiological significance of these findings remains to be determined.
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PMID:Cyclin-dependent kinase 5/Collapsin response mediator protein 2 pathway may mediate sevoflurane-induced dendritic development abnormalities in rat cortical neurons. 2844 71

Fetal alcohol spectrum disorders (FASD) represent a wide array of defects that arise from ethanol exposure during development. However, the underlying molecular mechanisms are limited. In the current report, we aimed to further evaluate the cannabinoid receptor type 1 (CB1R)-mediated mechanisms in a postnatal ethanol-exposed animal model. We report that the exposure of postnatal day 7 (P7) mice to ethanol generates p25, a CDK5-activating peptide, in a time- and CB1R-dependent manner in the hippocampus and neocortex brain regions. Pharmacological inhibition of CDK5 activity before ethanol exposure prevented accumulation of cleaved caspase-3 (CC3) and hyperphosphorylated tau (PHF1) (a marker for neurodegeneration) in neonatal mice and reversed cAMP response element-binding protein (CREB) activation and activity-regulated cytoskeleton-associated protein (Arc) expression. We also found that postnatal ethanol exposure caused a loss of RhoGTPase-related, Rac1, gene expression in a CB1R and CDK5 activity-dependent manner, which persisted to adulthood. Our epigenetic analysis of the Rac1 gene promoter suggested that persistent suppression of Rac1 expression is mediated by enhanced histone H3 lysine 9 dimethylation (H3K9me2), a repressive chromatin state, via G9a recruitment. The inhibition of CDK5/p25 activity before postnatal ethanol exposure rescued CREB activation, Arc, chromatin remodeling and Rac1 expression, spatial memory, and long-term potentiation (LTP) abnormalities in adult mice. Together, these findings propose that the postnatal ethanol-induced CB1R-mediated activation of CDK5 suppresses Arc and Rac1 expression in the mouse brain and is responsible for persistent synaptic plasticity and learning and memory defects in adult mice. This CB1R-mediated activation of CDK5 signaling during active synaptic development may slow down the maturation of synaptic circuits and may cause neurobehavioral defects, as found in this FASD animal model.
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PMID:CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol. 3014 82

Abnormal activation of cyclin-dependent kinase 5 (Cdk5) is associated with pathophysiological conditions. Ischemic preconditioning (IPC) can provide neuroprotective effects against subsequent lethal ischemic insult. The objective of this study was to determine how Cdk5 and related molecules could affect neuroprotection in the hippocampus of gerbils after with IPC [a 2-min transient cerebral ischemia (TCI)] followed by 5-min subsequent TCI. Hippocampal CA1 pyramidal neurons were dead at 5 days post-TCI. However, treatment with roscovitine (a potent inhibitor of Cdk5) and IPC protected CA1 pyramidal neurons from TCI. Expression levels of Cdk5, p25, phospho (p)-Rb and p-p53 were increased in nuclei of CA1 pyramidal neurons at 1 and 2 days after TCI. However, these expressions were attenuated by roscovitine treatment and IPC. In particular, Cdk5, p-Rb and p-p53 immunoreactivities in their nuclei were decreased. Furthermore, TUNEL-positive CA1 pyramidal neurons were found at 5 days after TCI with increased expression levels of Bax, PUMA, and activated caspase-3. These TUNEL-positive cells and increased molecules were decreased by roscovitine treatment and IPC. Thus, roscovitine treatment and IPC could protect CA1 pyramidal neurons from TCI through down-regulating Cdk5, p25, and p-p53 in their nuclei. These findings indicate that down-regulating Cdk5 might be a key strategy to attenuate p53-dependent apoptosis of CA1 pyramidal neurons following TCI.
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PMID:Down-regulation of cyclin-dependent kinase 5 attenuates p53-dependent apoptosis of hippocampal CA1 pyramidal neurons following transient cerebral ischemia. 3150 63

Cognitive deficit is a prevalent and underestimated complication of diabetes, and the underlying cellular and molecular mechanisms are not well understood. Aberrant activity of cyclin-dependent kinase (Cdk)5 is implicated in a number of neurodegenerative diseases. The present study examined the role of Cdk5 in the progression of diabetes-related cognitive deficits. We showed that the Cdk5 protein expression and kinase activity were significantly increased in diabetic mice at 16 wk. In primary cultured hippocampal neurons exposed to 30 mM glucose, Cdk5 protein and kinase activity were also elevated in a time-dependent manner. Moreover, the high glucose exposure led to an aberrant Cdk5 activation due to its activator p25 that was cleaved from p35 by calpain. Both in diabetic mice and in cultured hippocampal neurons exposed to high glucose, inhibition of Cdk5 activity with roscovitine (Ros) or short hairpin RNA (shRNA) decreased the protein levels of cleaved caspase-3 and the ratio of Bax and Bcl-2. The apoptotic rate detected by TUNEL in vivo or Annexin V and propidium iodide staining for flow cytometry in vitro also had obvious reduction. In addition, high glucose exposure resulted in the increase of phosphorylated (phospho)-MAPK kinase (MKK)6, phospho-p38, and c-Jun, which were rescued by Ros or Cdk5 shRNA. It is more important that the cognitive deficits of diabetic mice were also effectively alleviated by Ros. These results indicate that aberrant Cdk5 activity triggered hippocampal neuron apoptosis by activating MKK6/p38 MAPK cascade in hyperglycemia. Inhibition of Cdk5 overactivation attenuates neuronal apoptosis and cognitive deficits and contributes to the relief of diabetic neurotoxicity in the brain.-Liu, W., Zhou, Y., Liang, R., Zhang, Y. Inhibition of cyclin-dependent kinase 5 activity alleviates diabetes-related cognitive deficits.
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PMID:Inhibition of cyclin-dependent kinase 5 activity alleviates diabetes-related cognitive deficits. 3168 75

Alzheimer's disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo efficacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (H2O2), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade.
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PMID:A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice. 3223 99


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