Objective:

To assess the neuroprotective effectiveness of Erucin (ERN) and its polymeric mixed micelles against 3-Nitropropionic acid-induced neurodegeneration.

Background:

The neuroprotective efficacy of ERN, a structural analog of the well-known neuroprotective chemical sulforaphane, against Huntington’s disease (HD) has not been studied.

Design/Methods:

In-vitro neuroprotective effect of ERN was assessed on the morphological alterations, cytofluorimetric mechanistic, and mRNA expression level analyses against 3-NPA-intoxicated SH-SY5Y cells mimicking HD. Additionally, ERN-loaded mixed micelles were prepared, optimized by central composite design and structurally characterized by Dynamic light scattering (DLS), FTIR and TEM. Furthermore, in-vivo neuroprotective effects of ERN and its nanocarrier based formulation against the striatal toxicity caused by 3-NPA were tested in male Wistar rats.

Results:

In SH-SY5Y cells, pre-treatment with ERN reduced redox impairment, apoptotic status and mitochondrial dysfunction. RT-qPCR analysis revealed that pre-treatment of ERN, effectively protected neuronal cells against 3-NPA-induced cell death by preventing caspase-3 activation, BDNF upregulation and Nrf2 induction. The formulation of mixed micelles improved the ERN solubility and oral bioavailability. 3-NPA neurotoxicity significantly impaired learning and locomotor performance, elevated oxidative stress, neuroinflammation, neurotransmitters imbalance, excitotoxicity, mitochondrial dysfunction and HD-specific striatal lesions in rats. However, pre-administration of ERN and its polymeric micelles considerably boosted GABA, and reduced amount of glutamate content. The antioxidant ability of ERN was demonstrated by activation of Nrf2 and GSH levels. Besides, neuroinflammation status was maintained by blocking NF-kB with a concurrent decrease in pro-inflammatory enzymes (COX-2; iNOS) and cytokines (TNF-α and IL-6).  Likewise, caspase-3 was downregulated owing to ERN-induced anti-apoptotic effects and neurogenesis was promoted via activation of BDNF-TrkB-CREB signaling. 

Conclusions:

The observed neuroprotective effects could be attributed to enhanced mitochondrial activity as well as antioxidant, anti-inflammatory, and anti-apoptotic capabilities of ERN. Therefore, treating Huntington's disease with the dietary phytochemical ERN and its mixed micelles may reveal a new paradigm in development of plant-based drugs that combat neurodegeneration.