Objective: To demonstrate the effects of an oral, anti-inflammatory agent, NE3107, on motor activity, levodopa-induced dyskinesia (LID) induction, and neuron survival in a marmoset model of Parkinson’s disease (PD)

Background: Dopaminergic cell death in the substantia nigra is accompanied by compromised motor control in PD. Chronic neuroinflammation and oxidative stress are thought to be primary drivers of PD. Levodopa administration restores motor control but lacks disease-modifying potential and can cause dyskinesia (LID). NE3107 is an oral, blood-brain barrier–permeable molecule that binds extracellular signal-regulated kinase (ERK) in pathology-specific signaling pathways and inhibits ERK activation and downstream inflammatory cascades, without affecting homeostasis.

Method: In this 14-week study, marmosets aged 2-5 years underwent a 4-week observation period then received subcutaneous 6.5 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in fractionated doses during weeks 5 and 6 to induce parkinsonism. The animals were randomized to vehicle, NE3107 (30 mg/kg daily), or amantadine (1 mg/kg daily) treatment in week 8. Levodopa was initiated in all animals in week 10, and high doses of levodopa (12.5 mg/kg twice daily) were subsequently used to induce LID. Mean immobility scores were assessed starting from week 7. The effects of treatment on LID were evaluated in week 12. At the end of week 14, the animals were euthanized for brain immunohistochemical analyses.

Results: NE3107 monotherapy was associated with significantly improved mobility compared to vehicle or amantadine. Co-administration of NE3107 and levodopa significantly improved mobility, compared to monotherapy with either agent, and was associated with a significant reduction of LID. Additionally, NE3107-treated animals had two-fold more surviving tyrosine hydroxylase (TH) positive neurons, compared to controls.

Conclusion: Our results indicate the potential of anti-inflammatory‒mediated motor control by NE3107, improved benefit in combination with levodopa, and reduction of LID and TH loss. These observations support the hypothesized role of inflammation in the pathophysiology of motor impairment and LID in PD and the investigation of NE3107 in human clinical trials as a disease-modifying therapy for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effects-of-ne3107-anti-inflammatory-treatment-on-motor-activity-and-neurodegenerative-features-of-parkinsons-disease-in-a-marmoset-monkey-model/