Therapeutic effects of TP5, a Cdk5/p25 inhibitor, in in vitro and in vivo models of Parkinson's disease.

Parkinson's Disease (PD) is a chronic progressive neurodegenerative disease. Current treatments for PD are symptomatic and only increase striatal dopamine levels. Proactive neuroprotective approaches that slow the progression of PD and maintain appropriate dopamine neuron populations are needed to treat the disease. One suggested mechanism contributing to the pathology of PD involves the binding of cyclin-dependent kinase 5 (Cdk5) to p25, creating a hyperactivated complex to induce cell death. The objective of this study is to investigate the neuroprotective and neurorestorative properties of Truncated Peptide 5 (TP5), a derivative of the p35 activator involved in Cdk5 regulation, via the inhibition of Cdk5/p25 complex function. SH-SY5Y cell line and the nematode Caenorhabditis elegans were exposed to paraquat (PQ), an oxidative stressor, to induce Parkinsonian phenotypes. TP5 was administered prior to PQ exposure to determine its neuroprotective effects and, in further experiments, after PQ exposure to examine its neurorestorative effects. In the SH-SY5Y cell line, TP5 was found to have neuroprotective effects using a cell viability assay and demonstrated neuroprotective and neurorestorative effects in C. elegans by examining dopaminergic neurons and dopamine-dependent behaviour. TP5 decreased elevated Cdk5 activation in worms that were exposed to PQ. TP5's inhibition of Cdk5/p25 hyperactivity led to the protection of dopamine neurons in these PD models. This suggests that TP5 can act as a potential therapeutic drug towards PD.

Tran J ，Taylor SKB ，Gupta A ，Amin N ，Pant H ，Gupta BP ，Mishra RK ... -  《-》

TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease.

Binukumar BK ，Pant HC 《-》

Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer's disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 -hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson's disease.

Binukumar BK ，Shukla V ，Amin ND ，Grant P ，Bhaskar M ，Skuntz S ，Steiner J ，Pant HC ... -  《-》

TP5: A Novel Therapeutic Approach Targeting Aberrant and Hyperactive CDK5/p25 for the Treatment of Colorectal Carcinoma.

Amin N ，Wang H ，Song Q ，Bhaskar M ，Yadav SP ，Gilbert MR ，Pant H ，Tabouret E ，Zhuang Z ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Cdk5/p25 specific inhibitory peptide TFP5 rescues the loss of dopaminergic neurons in a sub-acute MPTP induced PD mouse model.

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.

Zhang Q ，Xie H ，Ji Z ，He R ，Xu M ，He Y ，Huang J ，Pan S ，Hu Y ... -  《-》