Guanosine improves motor behavior, reduces apoptosis, and stimulates neurogenesis in rats with parkinsonism

Abstract

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.

Guanosine and its role in neuropathologies

“…In this in vivo model of parkinsonism, a functional improvement (i.e., decrease in motor dysfunction) was detected in rats chronically treated with guanosine [38]. In addition to a reduction in apoptosis induced by this purine, this study also found that guanosine treatment caused an increase in the number of dopaminergic neurons in the substantia nigra as well as cell proliferation in the subventricular zone (SVZ).…”

“…We found that guanosine has antidepressant-like effects in these behavioral tests, decreasing the immobility time of mice in both the TST and the FST [173]. This effect was observed at doses (0.05-5 mg/kg, administered orally) lower than those commonly used in in vivo studies that have assessed its neuroprotective efficacy (around 8 mg/kg) [38,96,148]. Moreover, the use of specific pharmacological inhibitors suggested that these behavioral effects were dependent on the activation of the PI3K/Akt signaling pathway, as well as its downstream target mammalian target of rapamycin (mTOR) [173], an important regulator of protein synthesis that has been implicated in synaptogenesis and fast-acting antidepressant responses [174].…”

“…These actions seem to be mediated by the ability of this nucleoside to stimulate the astrocytic release of several endogenous regulators of survival, proliferation, and differentiation, including trophic factors such as nerve growth factor (NGF), transforming growth factor beta (TGFβ), and fibroblast growth factor 2 (FGF-2) [15,[37][38][39]. In addition, the release of these factors by guanosine may be related to the modulatory effects that this molecule has on astrocytic activity.…”

“…Indeed, given the neurotrophic effects of guanosine [15], it is not surprising that chronic administration of this nucleoside will influence cell proliferation and even neurogenesis in the injured brain. Although further studies are warranted to fully characterize which growth factors modulate the proliferation and neurogenic properties of guanosine, work by Su et al has suggested that FGF-2 may be one of the mediators of these effects [38]. In addition, a subsequent study by the same group has shown that guanosine stimulates neural stem cells through activation of cAMP and phosphorylation of cAMP response element-binding protein (CREB) [162], a transcription factor that mediates the expression of several proteins involved in the induction of neuroplasticity [163].…”

The Role of the Guanine-Based Purinergic System in Seizures and Epilepsy

“…administration of guanosine increased the amounts of both guanosine and guanine in the spinal cord, with a peak around 30 min [50]. Considering that extracellular guanine also exerts several biological effects [51,52], it is tempting to propose that some biological effects of guanosine may be regulated by its conversion to guanine by a membrane located purine nucleoside phosphorylase.…”