Early post-treatment with 9-cis retinoic acid reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson’s disease

Abstract

BackgroundRetinoic acid (RA) is a biologically active derivative of vitamin A. Previous studies have demonstrated that RA has protective effects against damage caused by H2O2 or oxygen-glucose deprivation in mesangial and PC12 cells. Pretreatment with 9-cis-retinoic acid (9cRA) reduced infarction and TUNEL labeling in cerebral cortex as well as attenuated neurological deficits after distal middle cerebral artery occlusion in rats. The purpose of this study was to examine a protective role of 9cRA in dopaminergic (DA) neurons in a typical rodent model of Parkinson’s disease (PD).ResultsThe protective role of 9cRA was first examined in rat primary ventromesencephalic culture. Treatment with 9cRA significantly reduced 6-hydroxydopamine (6-OHDA)-mediated cell death and TUNEL labeling in cultured dopaminergic neurons. The protective effect was also examined in adult male rats. Animals received unilateral 6-OHDA lesioning at the left medial forebrain bundle on day 0. Methamphetamine -induced rotational behavior was examined on days 6, 20 and 30 after lesioning. Animals were separated into 2 groups to balance rotational behavior and lesion extent on day 6 and were treated with either 9cRA or vehicle (i.c.v. on day 7 + intra-nasal from day 8 to day 14). Post-treatment with 9cRA significantly reduced methamphetamine –mediated ipislateral rotation at 20 and 30 days after lesioning. In vivo voltammetry was used to examine DA overflow in striatum. Treatment with 9cRA significantly increased KCl -evoked DA release in the lesioned striatum. 9cRA also increased tyrosine hydroxylase (+) cell number in the lesioned nigra as determined by unbiased stereology.ConclusionOur data suggests that early post-treatment with 9cRA has a protective effect against neurodegeneration in nigrostriatal DA neurons in an animal model of PD.

9-Cis Retinoic Acid Protects Against Methamphetamine-Induced Neurotoxicity in Nigrostriatal Dopamine Neurons

“…MA dose-dependently reduced TH (+) cell density (Fig 1A & D, p<0.001, F 2,62 =366.902, 2-Way ANOVA). Similar to our previous study (Yin et al, 2012), we found that treatment with 9cRA (50 nM) did not alter TH cell density in non-lesioned cells (Fig 1A & D, p=0.414, lower left panel). However, 9cRA significantly attenuated MA-induced loss of TH cells (Fig 1A lower right panel, and 1D, p=0.003 at 1 mM MA; p=0.007 at 2 mM MA, two way ANOVA + Newman-Keuls test).…”

“…RA attenuates 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium -mediated neurotoxicity in rats (Yin et al, 2012) and in SY5Y neuroblastoma cells (Cheung et al, 2009). The protective effect of RA in these cells involves the Akt pathway, increasing BCL2 while reducing p53 levels (Cheung et al, 2009; Tieu et al, 1999).…”

Mitochondrial control of cell bioenergetics in Parkinson’s disease

“…These symptoms are mainly associated with loss of dopaminergic neurons (DA) of the substantia nigra (SN). The mechanisms underlying DA death have been investigated in many cellular and animal models [2–7]. Mitochondrial dysfunction plays a key role in the development of PD [8, 9].…”

Morphogens and blood-brain barrier function in health and disease

“…However, a dysfunction in retinol or retinoic acid signaling in PD patients remains to be established. 55 In animal models of PD on the other hand, treatment with retinoic acid reduced degeneration of dopaminergic neurons 56 and alleviated motor symptoms. 57 Similar to PD, direct evidence for aberrant retinol/ retinoic acid signaling has not been found in multiple sclerosis.…”