Parkinson’s disease (PD) is a progressive neurological disorder characterized by motor deficits associated with nigrostriatal dopaminergic degeneration. Normal aging is the highest risk factor for developing PD. Current pharmacological and surgical treatments for PD are effective in improving symptoms, but do not prevent the progression of the disease. Neuregulins (NRGs) are pleiotrophic growth factors that are neurotrophic for dopamine cells in vitro and in vivo. In the present series of studies, the neuroprotective and neurorestorative roles of NRGs in the injured and aging nigrostriatal system were investigated.
In the first study, rats received 6-hydroxydopamine (6-OHDA) neurotoxin lesions to create an experimental model of PD, followed two weeks later by an infusion of the NRGs glial growth factor (GGF2) or neuregulin-2β (NRG-2β). The animals were assessed for cell survival and behavioral outcomes. The second study investigated age-related changes in NRG1 and its ErbB receptors in the chronologically aging rat mesostriatal system by Western blot and in situ hybridization. Animals were also infused with GGF2 in an aged model of PD to determine if NRG treatment was a potential therapy for the injured aged nigrostriatal system. The third study tested the hypothesis that reduction of ErbB4 receptor availability in the substantia nigra will exacerbate the detrimental effects of neurotoxin-induced damage upon the nigrostriatal system. ErbB4 expression was reduced in the substantia nigra using RNA interference followed by a striatal 6-OHDA lesion. The animals were then assessed for possible worsening of neurotoxin-induced motor dysfunction and dopaminergic cell death.
Results from the first study showed that infusion of either GGF2 or NRG-2β into the substantia nigra two weeks after striatal 6-OHDA injections significantly promoted functional recovery of motor function. In addition, both NRGs significantly increased the number of tyrosine hydroxylase (TH) neurons in the substantia nigra when compared to their appropriate controls. These findings demonstrate the neuroprotective and neurorestorative effects of NRGs administered after the establishment of experimental parkinsonism and identify NRG-2β as a novel neurotrophic agent for the dopaminergic nigrostriatal system. Results from the second study revealed a significant decrease in mRNA and protein for the functional NRG receptor ErbB4 and the dopaminergic biosynthetic enzyme TH in the substantia nigra of aging animals. The decrease in ErbB4 preceded that of TH. Reduced ErbB1 receptor protein was also observed in the ventral midbrain of aged rats. Despite the diminished availability of ErbB4 and ErbB1 receptors in the aging midbrian, supranigral GGF2 infusion was able to significantly protect against the morphological and behavioral deficits due to 6-OHDA lesion in an aging model of PD. These findings suggest that GGF2 administration may overcome the possible decline of NRG/ErbB trophic support for dopaminergic neurons in the injured aged midbrain. In the final study, knockdown of ErbB4 in vivo in the SNpc was achieved using a lentiviral vector-driven siRNA construct. This knockdown of ErbB4, however, did not exacerbate motor dysfunction or dopaminergic cell death in a model of experimental parkinsonism.
Overall, the results of this research demonstrate the neuroprotective and neurorestorative effects of NRGs in the injured and aged dopaminergic nigrostriatal system. Moreover, these findings indicate the potential therapeutic use of NRGs for the treatment of PD.