Exploring the neuroprotective effects of modafinil in a marmoset Parkinson model with immunohistochemistry, magnetic resonance imaging and spectroscopy.
Neuroprotective therapeutics stop or slow down the degeneration process in animal models of Parkinson's disease (PD). Neuronal survival in PD animal models is often measured by immunohistochemistry. However, dynamic changes in the pathology of the brain cannot be explored with this technique. Application of proton magnetic resonance (MR) imaging (MRI) and spectroscopy (MRS) can cover this lacuna as these techniques are non-invasive and can be repeated over time in the same animal. Therefore, the sensitivity of both techniques to measure changes in PD-pathology was explored in an experiment studying the neuroprotective effects of the vigilance enhancer modafinil in a marmoset PD model. Eleven marmoset monkeys were treated with the neurotoxin 1-methyl-1,2,3,6-tetrahydropyridine (MPTP). Six of these 11 animals, simultaneously, received a daily oral dose of modafinil (100 mg/kg) and five received vehicle for 27 days. MR experiments were performed at baseline and 1 and 3.5 weeks after the MPTP intoxication period after which brains were analyzed with immunohistochemistry. Tyrosine hydroxylase immunoreactive (TH-IR) staining of dopamine neurons of the substantia nigra pars compacta confirmed that modafinil was able to partially prevent the MPTP-induced neuronal damage. In MRS, N-acetylaspartate (NAA)/phosphocreatine (tCR) ratios confirmed the protective effect indicating that this is a sensitive measure to detect neuroprotection in the MPTP marmoset model. Furthermore, the number of TH-IR positive neurons and the NAA/tCR ratio were significantly correlated to behavioral observations indicating that the changes measured in the brain are also reflected in the behavior and vice versa.
van Vliet
S A M
SA
Department of Diagnosis and Therapy, TNO Defence, Security and Safety, Rijswijk, The Netherlands. s.a.m.van.vliet@med.umcg.nl
van Vlieta
S A M
SA
Blezer
E L A
EL
Jongsma
M J
MJ
Vanwersch
R A P
RA
Olivier
B
B
Philippens
I H C H M
IH
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D002144:Callithrix; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004334:Drug Administration Schedule; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D000077408:Modafinil; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000009:adverse effects; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010725:Phosphocreatine / Q000032:analysis / Q000378:metabolism; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001559:Benzhydryl Compounds; D015415:Biomarkers; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010725:Phosphocreatine; D001224:Aspartic Acid; C000179:N-acetylaspartate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D000077408:Modafinil; D004298:Dopamine