Objective: The objective was to determine whether Nilotinib crosses the blood brain barrier (BBB).

Background: Parkinson’s disease (PD) involves death of dopamine producing neurons in the Substantia Nigra Nigra pars compacta. Accumulation of alpha-Synuclein within intracellular inclusions known as Lewy bodies (LBs) is the pathological hallmark of Synucleinopathies, including PD, Lewy body dementia (LBD) and Multiple system atrophy (MSA). As PD progresses, Tau and beta-amyloid (Abeta) pathologies coincide with the onset of dementia, reminiscent of Alzheimer’s disease (AD).

Methods: Nilotinib concentration was measured in plasma and cerebrospinal fluid (CSF) at baseline, 2 months (interim) and 6 months. Pharmacodynamics analysis was performed to determine target engagement via measurement of CSF phosphorylated Abl (activity) in addition to neurodegeneration biomarkers, including α- Synuclein, dopamine breakdown by-product homovanillic acid (HVA), Total Tau and pTau181/231, Aβ42 and Aβ40. Cell death biomarkers, including CSF neuron specific enolase (NSE) and glial and neuronal marker S100B were measured.

Results: Nilotinib significantly reverses loss of CSF α-Synuclein and restores its plasma level to baseline. Nilotinib significantly increases the concentration of CSF homovanillic acid, suggesting an increase in central dopamine stores despite reduction of L-Dopa therapy. Nilotinib significantly alters CSF levels of total Tau and hyper-phosphorylated (p-Tau)231 and pTau181 and Aβ42 and Aβ40. Nilotinib significantly reduces CSF cell death markers, including neuron specific enolase (NSE) and S100B.

Conclusions: Pre-clinical data indicate that the tyrosine kinase Abl (Abelson) inhibitor Nilotinib penetrates the brain and induces autophagic clearance of alpha-Synuclein, hyper-phosphorylated Tau (p-Tau) and Abeta. The results of phase-I open label clinical trial of 12 participants taking 150mg and 300mg Nilotinib show a significant alteration in CSF biomarkers and increase of endogenous dopamine. Additionally, the apparent motor and cognitive outcomes may be attributed to reduction of neurotoxic proteins and/or the increase of endogenous dopamine via mesolimbic signaling to pre-frontal cortex. The data provide feasibility for multicenter, randomized, placebo-controlled, double blind studies in PD and other neurodegenerative diseases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nilotinib-significantly-alters-csf-biomarkers-and-increases-endogenous-dopamine-in-open-label-phase-i-clinical-trial-in-parkinsons-disease-with-dementia-and-lewy-body-dementia/