Nurr1, Pitx3, and α7 nAChRs mRNA Expression in Nigral Tissue of Rats with Pedunculopontine Neurotoxic Lesion

Abstract

Background and Objectives: The knowledge that the cholinergic neurons from pedunculopontine nucleus (PPN) are vulnerable to the degeneration in early stages of the Parkinson disease progression has opened new perspectives to the development of experimental model focused in pontine lesions that could increase the risk of nigral degeneration. In this context it is known that PPN lesioned rats exhibit early changes in the gene expression of proteins responsible for dopaminergic homeostasis. At the same time, it is known that nicotinic cholinergic receptors (nAChRs) mediate the excitatory influence of pontine-nigral projection. However, the effect of PPN injury on the expression of transcription factors that modulate dopaminergic neurotransmission in the adult brain as well as the α7 nAChRs gene expression has not been studied. The main objective of the present work was the study of the effects of the unilateral neurotoxic lesion of PPN in nuclear receptor-related factor 1 (Nurr1), paired-like homeodomain transcription factor 3 (Pitx3), and α7 nAChRs mRNA expression in nigral tissue. Materials and Methods: The molecular biology studies were performed by means of RT-PCR. The following experimental groups were organized: Non-treated rats, N-methyl-D-aspartate (NMDA)-lesioned rats, and Sham operated rats. Experimental subjects were sacrificed 24 h, 48 h and seven days after PPN lesion. Results: Nurr1 mRNA expression, showed a significant increase both 24 h (p < 0.001) and 48 h (p < 0.01) after PPN injury. Pitx3 mRNA expression evidenced a significant increase 24 h (p < 0.001) followed by a significant decrease 48 h and seven days after PPN lesion (p < 0.01). Finally, the α7 nAChRs nigral mRNA expression remained significantly diminished 24 h, 48 h (p < 0.001), and 7 days (p < 0.01) after PPN neurotoxic injury. Conclusion: Taking together these modifications could represent early warning signals and could be the preamble to nigral neurodegeneration events.

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“…Similarly, pontine injury is associated with compromised nigrostriatal redox homeostasis that can accentuate nigral vulnerability [14,15]. Also at the molecular level, our previous findings demonstrate changes in the gene expression of both transcription factors and genes involved in the phenotype and dopaminergic homeostasis that together suggest an increased risk condition more prone to degeneration [16,17].…”

Motor Coordination Disorders Evaluated through the Grid Test and Changes in the Nigral Nrf2 mRNA Expression in Rats with Pedunculopontine Lesion

“…This temporal behavior may be part of a mosaic of molecular events that involves the nigral gene expression of other genes, such as: the brain derived neurotrophic factor , key in the survival of nigral dopaminergic neurons, TH , VMAT and DAT , essential in maintaining dopaminergic homeostasis, as well as Nurr1 and Pitx3 , those that play a role in maintaining the dopaminergic phenotype [ 10 , 11 , 12 ].…”

“…Sample collection: Our group has already published the details of this procedure previously [ 12 ]. In brief, the dissections of the tissues were carried out under stereoscopic microscope (Wild Heerbrugg Stereo Microscopes, Heerbrugg, Switzerland).…”

“…Our group has published evidence supporting the concurrence of events that increase the risk to nigral degeneration together with molecular and biochemical changes, suggesting compensatory mechanisms at nigral level in rats with a neurotoxic lesion of PPN [ 9 , 10 , 11 , 12 ]. In this sense, our results showed the occurrence of oxidative stress events at the nigrostriatal level, concomitant with a decrease in the nigrostriatal mRNA expression of vesicular monoamine transporters (VMAT2) and the dopamine transporter (DAT) in PPN-lesioned rats [ 9 ].…”

“…Finally, our group also showed that PPN neurotoxic injury induces changes in the nigral gene expression of transcription factors, such as Nurr 1 and Pitx3, which participate in the maintenance of the phenotype and dopaminergic homeostasis in the adult brain [ 12 ].…”