Phenolic-rich extract of avocado Persea americana (var. Colinred) peel blunts paraquat/maneb-induced apoptosis through blocking phosphorylation of LRRK2 kinase in human nerve-like cells

Environ Toxicol. 2022 Mar;37(3):660-676. doi: 10.1002/tox.23433. Epub 2021 Dec 12.

Abstract

It is increasingly evident that LRRK2 kinase activity is involved in oxidative stress (OS)-induced apoptosis-a type of regulated cell death and neurodegeneration, suggesting LRRK2 inhibition as a potential therapeutic target. We report that a phenolic-rich extract of avocado Persea americana var. Colinred peel (CRE, 0.01 mg/ml) restricts environmental neurotoxins paraquat (1 mM)/maneb (0.05 mM)-induced apoptosis process through blocking reactive oxygen species (ROS) signaling and concomitant inhibition of phosphorylation of LRRK2 in nerve-like cells (NLCs). Indeed, PQ + MB at 6 h exposure significantly increased ROS (57 ± 5%), oxidation of protein DJ-1cys106SOH into DJ-1Cys106SO3 ([~3.7 f(old)-(i)ncrease]), augmented p-(S935)-LRRK2 kinase (~20-f(old) (i)ncrease), induced nuclei condensation/fragmentation (28 ± 6%), increased the expression of PUMA (~6.2-fi), and activated CASPASE-3 (CASP-3, ~4-fi) proteins; but significantly decreased mitochondrial membrane potential (ΔΨm, ~48 ± 4%), all markers indicative of apoptosis compared to untreated cells. Remarkably, CRE significantly diminished both OS-signals (i.e., DCF+ cells, DJ-1Cys106SO3) as well as apoptosis markers (e.g., PUMA, CASP-3, loss of ΔΨm, p-LRRK2 kinase) in NLCs exposed to PQ + MB. Furthermore, CRE dramatically reestablishes the transient intracellular Ca2+ flow (~300%) triggered by dopamine (DA) in neuronal cells exposed to PQ + MB. We conclude that PQ + MB-induced apoptosis in NLCs through OS-mechanism, involving DJ-1, PUMA, CASP-3, LRRK2 kinase, mitochondria damage, DNA fragmentation, and alteration of DA-receptors. Our findings imply that CRE protects NLCs directly via antioxidant mechanism and indirectly by blocking LRRK2 kinase against PQ + MB stress stimuli. These data suggest that CRE might be a potential natural antioxidant.

Keywords: Colinred; LRRK2; PF-06447475; Parkinson; avocado; maneb; neurodegeneration; oxidative stress; paraquat.

MeSH terms

  • Apoptosis
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Maneb*
  • Oxidative Stress
  • Paraquat / toxicity
  • Persea*
  • Phosphorylation
  • Plant Extracts / pharmacology

Substances

  • Plant Extracts
  • Maneb
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Paraquat