Guanosine improves motor behavior, reduces apoptosis, and stimulates neurogenesis in rats with parkinsonism.
Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) caused by an abnormal rate of apoptosis. Endogenous stem cells in the adult mammalian brain indicate an innate potential for regeneration and possible resource for neuroregeneration in PD. We previously showed that guanosine prevents apoptosis even when administered 48 hr after the toxin 1-methyl-4-phenylpyridinium (MPP(+)). Here, we induced parkinsonism in rats with a proteasome inhibitor. Guanosine treatment reduced apoptosis, increased tyrosine hydroxylase-positive dopaminergic neurons and expression of tyrosine hydroxylase in the SNc, increased cellular proliferation in the SNc and subventricular zone, and ameliorated symptoms. Proliferating cells in the subventricular zone were nestin-positive adult neural progenitor/stem cells. Fibroblast growth factor-2-expressing cells were also increased by guanosine. Thus, guanosine protected cells from apoptosis and stimulated "intrinsic" adult progenitor/stem cells to become dopaminergic neurons in rats with proteasome inhibitor-induced PD. The cellular/molecular mechanisms underlying these effects may open new avenues for development of novel therapeutics for PD.
Su
Caixin
C
Department of Surgery (Neurosurgery, Neurobiology), McMaster University, Health Sciences Centre, Hamilton, Ontario, Canada.
Elfeki
Nada
N
Ballerini
Patrizia
P
D'Alimonte
Iolanda
I
Bau
Christian
C
Ciccarelli
Renata
R
Caciagli
Francesco
F
Gabriele
Joseph
J
Jiang
Shucui
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001973:Bromodeoxyuridine; D004298:Dopamine / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006151:Guanosine / Q000627:therapeutic use*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D018696:Neuroprotective Agents; D016222:Fibroblast Growth Factor 2; D006151:Guanosine; D014446:Tyrosine 3-Monooxygenase; D001973:Bromodeoxyuridine; D004298:Dopamine