salubrinal and Parkinson-Disease

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.. 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.. 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.. 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.

Topics: Animals; Cinnamates; Lipopolysaccharides; Microglia; Neuroinflammatory Diseases; NF-kappa B; Parkinson Disease; Rats; Substantia Nigra; Thiourea

Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately validated in cell-based models of neuronal loss and provide a foundation for establishing systemically active SUMO activators to treat degenerative diseases such as Parkinson's disease, Alzheimer's disease, and stroke.

Topics: Alzheimer Disease; Benzothiazoles; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Molecular Structure; Neuroprotective Agents; Parkinson Disease; Quinolines; Small Molecule Libraries; Small Ubiquitin-Related Modifier Proteins; Stroke; Structure-Activity Relationship; Sumoylation; Thiazoles