Novel Molecules for Neuroprotection in Experimental Parkinsonism
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Novel Molecules for Neuroprotection in Experimental Parkinsonism
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| Creator |
Ngumbau, Nthenge Dominic
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| Subject |
Cell Biology & Physiology
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| Description |
Neurodegeneration of the substantia nigra (SN) particularly its pars compacta (SNpc) region disrupts control of motor function, as seen in Parkinson's disease (PD). Nigrostriatal dopaminergic denervation results in decreased dopamine levels in the striatum translating to inadequate dopaminergic signalling. Dopaminergic receptor signalling employs cAMP as a secondary messenger whose levels are regulated by cAMP degrading phosphodiesterase (PDE).
Differentiated SH-SY5Y neuronal cell-lines were used to check novel drug candidates against parkinsonian neurotoxin (1-Methyl 4-Phenylpyridinium (MPP+))-induced neuronal cell death. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated mouse model of Parkinson's disease was used to assess the molecules’ effect on behavioural motor function using akinesia, catalepsy, swim, pole, open field and rotarod tests with ANY-maze software, cAMP levels in the striatum by spectrophotometric ELISA, PDE inhibitory activity by radiometric enzyme assay, striatal dopamine and serotonin neurochemistry as well as hydroxyl radical estimation by HPLC-electrochemistry and dopaminergic neuron survival in the SN by tyrosine hydroxylase immunohistochemistry.
Irsogladine was found to possess desirable characteristics such as: crossing of the blood brain barrier, PDE inhibitory property, radical scavenging ability, protection against striatal DA depletion, rescue SNpc dopaminergic neurons against degeneration and finally MPTP-induced behavioural dysfunctions. Four derivatives of Irsogladine; JVIR1, JVIR2, JVIR3 and PJD9 also show protection in the MPTP model demonstrating that shifting the Cl at position 5 to the 4th position of the dichlorophenyl ring of Irsogladine to aquire 6-(2,4-dichlorophenyl)-1,3,5-triazine-2,4-diamine (JVIR1) or removing both the Cl atoms on the dichlorophenyl ring of Irsogladine and replacing them with a single Br at the 2nd position of the phenyl ring to get 6-(2-bromophenyl)-1,3,5-triazine-2,4-diamine (JVIR2) or a single Br at the 4th position of the phenyl ring to yield 6-(4-bromophenyl)-1,3,5-triazine-2,4-diamine (JVIR3) or removal of all the halogens on the phenyl ring to get 6-phenyl-1,3,5-triazine-2,4-diamine (PJD9) does not interfere with the antiparkinsonian activity of the general structure or at least does not lead to loss of anti-parkinsonian activity. Removal of the phenyl ring and replacing it with either a methyl or methyl indolyl group to get PJD8 and PJD10 resulted in reduced antiparkinsonian activity. PJD8 and PJD10 probably do not influence striatal dopaminergic signalling via the elevation of cAMP and or DA. The two molecules do demonstrate marginal rescue from parkinsonian phenotype at the highest doses and further investigation on the underlying mechanism would help in lowering the doses or enhancing their activity.
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| Date |
2016
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2582/1/NTHENGE_DOMINIC_N___THESIS.pdf
Ngumbau, Nthenge Dominic (2016) Novel Molecules for Neuroprotection in Experimental Parkinsonism. PhD thesis, C U. |
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| Relation |
http://www.eprints.iicb.res.in/2582/
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