Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson's disease.

Abstract

BACKGROUND:

Parkinson's disease (PD) is one of the most common causes of dementia and motor deficits in the elderly. PD is characterized by the abnormal accumulation of the synaptic protein alpha-synuclein (α-syn) and degeneration of dopaminergic neurons in substantia nigra, which leads to neurodegeneration and neuroinflammation. Currently, there are no disease modifying alternatives for PD; however, targeting neuroinflammation might be a viable option for reducing motor deficits and neurodegeneration. Lenalidomide is a thalidomide derivative designed for reduced toxicity and increased immunomodulatory properties. Lenalidomide has shown protective effects in an animal model of amyotrophic lateral sclerosis, and its mechanism of action involves modulation of cytokine production and inhibition of NF-κB signaling.

METHODS:

In order to assess the effect of lenalidomide in an animal model of PD, mThy1-α-syn transgenic mice were treated with lenalidomide or the parent molecule thalidomide at 100 mg/kg for 4 weeks.

RESULTS:

Lenalidomide reduced motor behavioral deficits and ameliorated dopaminergic fiber loss in the striatum. This protective action was accompanied by a reduction in microgliosis both in striatum and hippocampus. Central expression of pro-inflammatory cytokines was diminished in lenalidomide-treated transgenic animals, together with reduction in NF-κB activation.

CONCLUSION:

These results support the therapeutic potential of lenalidomide for reducing maladaptive neuroinflammation in PD and related neuropathologies.

• Authors: Elvira Valera, Michael Mante, Scott Anderson, Edward Rockenstein, Eliezer Masliah
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 12 Pg. 93 (May 14 2015) ISSN: 1742-2094 [Electronic] England
• PMID: 25966683 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Glial Fibrillary Acidic Protein
• Immunologic Factors
• RNA, Messenger
• alpha-Synuclein
• Thalidomide
• Lenalidomide
• Dopamine

Topics

• Analysis of Variance
• Animals
• Cell Line, Transformed
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Dopamine (metabolism)
• Glial Fibrillary Acidic Protein (metabolism)
• Immunologic Factors (pharmacology, therapeutic use)
• Lenalidomide
• Mental Disorders (drug therapy, etiology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (drug effects)
• Parkinson Disease (complications, genetics)
• RNA, Messenger (metabolism)
• Signal Transduction (drug effects, genetics)
• Thalidomide (analogs & derivatives, pharmacology, therapeutic use)
• alpha-Synuclein (genetics, metabolism)