Intrastriatal Infusion of Liver Growth Factor Stimulates Dopamine Terminal Sprouting and Partially Restores Motor Function in 6-Hydroxydopamine-lesioned Rats

Abstract

Liver growth factor (LGF) is a mitogen for liver cells that shows biological activity in extrahepatic sites and may be useful for neuroregenerative therapies. The aim of this work was to investigate the effects of the intrastriatal (IS) infusion of LGF in the 6-hydroxydopamine rat model of Parkinson's disease. Tyrosine hydroxylase-positive innervation was significantly increased in the dopamine-denervated striatum of rats receiving intrastriatal LGF infusions (160 ng/day/rat × 15 days) as compared with a vehicle-infused group. There was no evidence of dopaminergic neurogenesis in the striatum or substantia nigra in any experimental group at the times studied. However, in those animals undergoing IS-LGF infusion for 48 hr, we found a significant increase in both microglial proliferation and in the number of microglial cells that acquired the ameboid morphology. This is characteristic of activated microglia/macrophages that has been reported to play an important role in dopamine terminal sprouting. In summary, our study shows that IS infusion of LGF stimulates the outgrowth of tyrosine hydroxylase-positive terminals in the striatum of 6-hydroxydopamine-treated rats. As apomorphine-induced rotational behavior was also reduced in these animals, we propose LGF as a novel factor that, when delivered to the striatum, may be useful in the treatment of Parkinson's disease.

Liver growth factor treatment restores cell-extracellular matrix balance in resistance arteries and improves left ventricular hypertrophy in SHR

“…In fact, they were completely restored to levels not different from those found in WKY normotensive rats. Second, the actions of LGF in vitro on VSMC were very rapid, in 48 h, a time course effect similar that found in liver (27) and in the striatum (52), suggesting that the first actions of LGF might be on cell/ECM balance, which in turn has a favorable impact on vascular and heart mechanics, reducing blood pressure. In the study of new antihypertensive treatments, to address the chicken and egg question, it has been common to include a group of animals treated with a general vasodilator, such as hydralazine or hydrochlorothiazide, or a combination of both.…”

“…We have previously demonstrated that the excessive ECM deposition by VSMC from SHR is related to a cellular defect in SHR, consisting of defective proliferation, but enhanced cell survival of hypertrophied diploid cells, which keep producing ECM, without normal turnover (7). On the other hand, the regenerative actions of LGF in several biological systems have been linked to its mitogenic effects (26,27,35,52). In our previous study, we also reported that LGF was able to improve the reduced VSMC density and abnormally high ploidy in carotid arteries from SHR.…”

“…These data suggest that blood pressure-lowering effects on its own do not have such a big impact in MRA wall mechanical properties, supporting the idea that LGF has a mechanism of action other than vasodilatation. In spite of the evidence of a quick effect of LGF on vascular composition, we cannot exclude other possible actions of LGF on blood pressure regulation, particularly at a central level, since there is evidence that LGF is able to act on the central nervous system (52), and SHR exhibit abnormalities in sympathoexcitatory neurons (15), hypereactivity of the brain renin-angiotensin-system, and reduced arterial baroreflex function (68).…”

“…The aim of the present study has been to gain further insight in the regenerative cardiovascular actions of LGF treatment in SHR, assessing its effects on intramyocardial and mesenteric resistance arteries (MRA) and LVH. Furthermore, we have investigated if the restoration of arterial cell/ECM disbalance by this factor is linked to a mitogenic effect on vascular smooth muscle cells (VSMC), as previously described in other cell types (26,35,52). …”

“…The chemical analysis of LGF obtained from human and rat plasma has revealed that it is a covalently bound albumin-bilirubin complex (24,25). The regenerative effects of LGF, initially described in hepato-biliary disorders (22,23,26), have been recently extended to other diseases, such as Parkinson's disease (35,52), testicular degeneration (51), and pulmonary fibrosis (47).…”