KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background and Purpose</jats:title><jats:p>Monoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinson’s disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>We designed and synthesized α-aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>KDS2010 showed the highest potency, specificity, and reversibility among the α-aminoamide derivatives, with high bioavailability (&gt;100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and Implications</jats:title><jats:p>KDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD.</jats:p></jats:sec><jats:sec><jats:title>Representative Schematic</jats:title><jats:fig id="ufig1" position="anchor" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="190579v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec><jats:sec><jats:title>What is already known</jats:title><jats:p>KDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor.</jats:p><jats:p>MAO-B is critical for PD pathology through astrocytic GABA and H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> synthesis.</jats:p></jats:sec><jats:sec><jats:title>What this study adds</jats:title><jats:p>KDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD.</jats:p><jats:p>KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates.</jats:p></jats:sec><jats:sec><jats:title>What is the clinical significance?</jats:title><jats:p>KDS2010 is a safe and promising therapeutic candidate for Parkinson’s disease.</jats:p><jats:p>Reversible MAO-B inhibitors could be more effective for treatment of Parkinson’s disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.</jats:p></jats:sec>

Adenovirus-induced Reactive Astrogliosis Exacerbates the Pathology of Parkinson’s Disease

“…Moreover, reactive astrocytes have been reported to directly cause neuronal death via H 2 O 2 [ 13 ] and lipocalin-2 [ 14 ]. Blocking reactive astrogliosis by pharmacologic inhibition of monoamine oxidase-B, which is the key enzyme for astrocytic GABA and H 2 O 2 synthesis and astrogliosis [ 11 , 15 - 17 ], significantly reverses or prevents the PD pathology and parkinsonian motor symptoms [ 11 , 18 ]. These previous reports together suggest an idea that inducing reactive astrogliosis can exacerbate PD pathology and motor dysfunction.…”