The beneficial effect of salubrinal on neuroinflammation and neuronal loss in intranigral LPS-induced hemi-Parkinson disease model in rats

Abstract

Objective

Endoplasmic reticulum stress (ERS) and neuroinflammation are triggers for neurodegenerative disorders. Salubrinal is a selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phosphorylated eukaryotic initiation factor-2α (eIF2α), the key crucial pathway in the ERS. Therefore, this study assessed the effects of inhibition of the ERS with salubrinal in the intranigral hemi-Parkinson disease (PD) model.

Materials and methods

Animals were treated with salubrinal for one week after the PD model was created by intranigral lipopolysaccharide (LPS) administration. Apomorphine-induced rotation, rotarod, cylinder, and pole tests were performed to evaluate behavioral changes. Proinflammatory cytokines and the expression level of the dual specificity protein phosphatase 2 (DUSP2), PP1, and p-eIF2α were evaluated. Nigral expression of inducible nitric oxide synthase (iNOS), nuclear factor kappaB (Nf-κB), and cyclooxygenase (COX)-2 was determined. Finally, tyrosine hydroxylase and caspase-3/ caspase-9 expressions were assessed by immunohistochemistry.

Results

Salubrinal reduced the motor impairments and dopamine-related behavioral deficiencies caused by the LPS. Salubrinal attenuated the LPS-induced increased levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and salubrinal rescued the loss of TH expression and dopamine levels and prevented the caspase-3/9 increase in the substantial nigra (SN). LPS potently increased iNOS, Nf-κB, and COX-2 expression, but this effect was reduced after salubrinal treatment. Additionally, salubrinal attenuated the LPS-induced PP1 and DUSP2 increase.

Conclusion

Our results reveal that salubrinal is attenuating several inflammatory mediators and thereby decreased the inflammatory effects of LPS in the neurons of the SN. Together this results in increased cellular survival and maintained integrity of SN. Taken together our data show the beneficial effects of inhibition of ERS to restrict neuroinflammatory progression and neuronal loss in a PD model.

Keywords:

• Endoplasmic reticulum stress
• salubrinal
• Parkinson’s disease
• LPS

Author contributions

Conceptualization: FNC, CG, SSB, and AK; Data curation: FNC, CG, and MSK; Formal analysis: FNC, CG, ET, and OO; Investigation: FNC and CG; Methodology: FNC, CG, SSB and AK; Resources: FNC, CGand AK; Animal Study: FNC, CGand SŞ; Supervision: FNC, SSB and AK; Validation: FNCand CG; Visualization: FNC, MSK and CG; Roles/Writing-original draft: FNC, MSK, CG and AK; Writing-review and editing: FNC, MSK, CG, SŞ, SSB, OO, ET, and AK.

Disclosure statement

No potential conflict of interest was reported by the authors.