Abstract
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by a complex network of physiopathological events where oxidative stress plays a central role among other factors such as neuroinflammation and protein homeostasis. Nuclear factor-erythroid 2 p45-related factor 2 (NRF2) has a multitarget profile itself as it controls a plethora of cellular processes involved in the progression of the disease. In this line, we designed a novel family of 2-(1H-indol-3-yl)ethan-1-amine derivatives as NRF2 inducers with complementary activities. Novel compounds are based on melatonin scaffold and include, among other properties, selective monoamine oxidase B (MAO-B) inhibition activity. Novel multitarget compounds exhibited NRF2 induction activity and MAO-B selective inhibition, combined with anti-inflammatory, antioxidant, and blood–brain barrier permeation properties. Furthermore, they exert neuroprotective properties against oxidative stress toxicity in PD-related in vitro. Hit compound 14 reduced oxidative stress markers and exerted neuroprotection in rat striatal slices exposed to 6-hydroxydopamine or rotenone. In conclusion, we developed a promising family of dual NRF2 inducers and selective MAO-B inhibitors that could serve as a novel therapeutic strategy for PD treatment.
Highlights
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, affecting 2–3% population aged 65 years or over [1]
PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), dopamine levels reduction and the presence of α-synuclein protein deposits known as Lewy bodies [1,2,3,4]
PD etiology remains unknown, evidence indicates that oxidative stress (OS) plays an essential role in its onset and development, associated with other pathological pathways, including α-synuclein proteostasis, mitochondrial dysfunction, calcium dyshomeostasis, axonal transport dysfunction, and neuroinflammation
Summary
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, affecting 2–3% population aged 65 years or over [1]. PD etiology remains unknown, evidence indicates that oxidative stress (OS) plays an essential role in its onset and development, associated with other pathological pathways, including α-synuclein proteostasis, mitochondrial dysfunction, calcium dyshomeostasis, axonal transport dysfunction, and neuroinflammation. Crosstalk between these factors induces increased OS, creating a feedback loop that accelerates neurodegeneration [1,5]. Current PD therapies are merely symptomatic, highlighting the need for effective treatments able to modify disease progression. PD treatments include monoamine oxidase (MAO) inhibitors (selegiline, rasagiline, and safinamide [6]) directed to increasing dopamine levels at the synaptic clef
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