Executive function deficits and glutamatergic protein alterations in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

Changes in executive function are at the root of most cognitive problems associated with Parkinson's disease. Because dopaminergic treatment does not necessarily alleviate deficits in executive function, it has been hypothesized that dysfunction of neurotransmitters/systems other than dopamine (DA) may be associated with this decrease in cognitive function. We have reported decreases in motor function and dopaminergic/glutamatergic biomarkers in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's mouse model. Assessment of executive function and dopaminergic/glutamatergic biomarkers within the limbic circuit has not previously been explored in our model. Our results show progressive behavioral decline in a cued response task (a rodent model for frontal cortex cognitive function) with increasing weekly doses of MPTP. Although within the dorsolateral (DL) striatum mice that had been given MPTP showed a 63% and 83% loss of tyrosine hydroxylase and dopamine transporter expression, respectively, there were no changes in the nucleus accumbens or medial prefrontal cortex (mPFC). Furthermore, dopamine-1 receptor and vesicular glutamate transporter (VGLUT)-1 expression increased in the mPFC following DA loss. There were significant MPTP-induced decreases and increases in VGLUT-1 and VGLUT-2 expression, respectively, within the DL striatum. We propose that the behavioral decline following MPTP treatment may be associated with a change not only in cortical-cortical (VGLUT-1) glutamate function but also in striatal DA and glutamate (VGLUT-1/VGLUT-2) input.

MPTP-induced parkinsonism in mice alters striatal and nigral xCT expression but is unaffected by the genetic loss of xCT.

Nigral cell loss in Parkinson's disease (PD) is associated with disturbed glutathione (GSH) and glutamate levels, leading to oxidative stress and excitotoxicity, respectively. System xc- is a plasma membrane antiporter that couples cystine import (amino acid that can be further used for the synthesis of GSH) with glutamate export to the extracellular environment, and can thus affect both oxidative stress and glutamate excitotoxicity. In the current study, we evaluated the involvement of system xc- in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Our results indicate that the expression of xCT (the specific subunit of system xc-) undergoes region-specific changes in MPTP-treated mice, with increased expression in the striatum, and decreased expression in the substantia nigra. Furthermore, mice lacking xCT were equally sensitive to the neurotoxic effects of MPTP compared to wild-type (WT) mice, as they demonstrate similar decreases in striatal dopamine content, striatal tyrosine hydroxylase (TH) expression, nigral TH immunopositive neurons and forelimb grip strength, five weeks after commencing MPTP treatment. Altogether, our data indicate that progressive lesioning with MPTP induces striatal and nigral dysregulation of system xc-. However, loss of system xc- does not affect MPTP-induced nigral dopaminergic neurodegeneration and motor impairment in mice.

Cyclosporin promotes neurorestoration and cell replacement therapy in pre-clinical models of Parkinson's disease.

BACKGROUND: The early clinical trials using fetal ventral mesencephalic (VM) allografts in Parkinson's disease (PD) patients have shown efficacy (albeit not in all cases) and have paved the way for further development of cell replacement therapy strategies in PD. The preclinical work that led to these clinical trials used allografts of fetal VM tissue placed into 6-OHDA lesioned rats, while the patients received similar allografts under cover of immunosuppression in an α-synuclein disease state. Thus developing models that more faithfully replicate the clinical scenario would be a useful tool for the translation of such cell-based therapies to the clinic. RESULTS: Here, we show that while providing functional recovery, transplantation of fetal dopamine neurons into the AAV-α-synuclein rat model of PD resulted in smaller-sized grafts as compared to similar grafts placed into the 6-OHDA-lesioned striatum. Additionally, we found that cyclosporin treatment was able to promote the survival of the transplanted cells in this allografted state and surprisingly also provided therapeutic benefit in sham-operated animals. We demonstrated that delayed cyclosporin treatment afforded neurorestoration in three complementary models of PD including the Thy1-α-synuclein transgenic mouse, a novel AAV-α-synuclein mouse model, and the MPTP mouse model. We then explored the mechanisms for this benefit of cyclosporin and found it was mediated by both cell-autonomous mechanisms and non-cell autonomous mechanisms. CONCLUSION: This study provides compelling evidence in favor for the use of immunosuppression in all grafted PD patients receiving cell replacement therapy, regardless of the immunological mismatch between donor and host cells, and also suggests that cyclosporine treatment itself may act as a disease-modifying therapy in all PD patients.