title: Neuroprotective effect of the chemical chaperone, trehalose in a chronic MPTP-induced Parkinson's disease mouse model.
abstract: Parkinson's disease (PD) is a progressive motor disease of unknown etiology in the majority of cases. The clinical features of PD emerge due to selective degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), which project to the caudate putamen (CPu) where they release DA. In the current in vivo mouse model study, we tested trehalose for its ability to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage to DA neurons. Trehalose is a naturally occurring disaccharide present in plants and animals and appears capable of protecting cells against various environmental stresses. The effect of trehalose is likely due to its action as a pharmacological chaperone which promotes protein stability. In the present study, there were four treatment groups: saline only (control); probenecid only; MPTP+probenecid; and trehalose+MPTP+probenecid. MPTP-induced losses in tyrosine hydroxylase and DA transporter immunoreactivity in the ventral midbrain SNc and CPu were significantly reduced by trehalose. Decreases in CPu dopamine levels produced by MPTP were also blocked by trehalose. Microglial activation and astrocytic hypertrophy induced by MPTP were greatly reduced by trehalose, indicating protection against neuroinflammation. These effects are commensurate with the observed trehalose sparing of motor deficits produced by MPTP in this mouse model. Two tight junctional proteins, ZO-1 and occludin, are downregulated following MPTP treatment and trehalose blocks this effect. Likewise, the glucose transporter-1 that is expressed in brain endothelial cells is also protected by trehalose from MPTP-induced down-regulation. This study is the first to demonstrate using fluoro-turoquoise FT gel perfusion techniques, the protection afforded by trehalose from MPTP-induced damage to microvessels and endothelial and suggests that trehalose therapy may have the potential to slow or ameliorate PD pathology.
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, United States. Electronic address: Sumit.Sarkar@FDA.hhs.gov.
authors: Sumit
authors: S
authors: Sarkar
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, United States.
authors: Srinivasulu
authors: S
authors: Chigurupati
authors: Toxicology Pathology Associates, Jefferson, AR 72079, United States.
authors: James
authors: J
authors: Raymick
authors: Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Dushyant
authors: D
authors: Mann
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, United States.
authors: John F
authors: JF
authors: Bowyer
authors: Division of Systems Biology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, United States.
authors: Tom
authors: T
authors: Schmitt
authors: Division of Systems Biology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, United States.
authors: Richard D
authors: RD
authors: Beger
authors: Office of Testing & Research, CDER/FDA, White Oak, MD 20993, United States.
authors: Joseph P
authors: JP
authors: Hanig
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, United States.
authors: Larry C
authors: LC
authors: Schmued
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, United States.
authors: Merle G
authors: MG
authors: Paule
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000098:blood supply / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism / Q000517:prevention & control; D005904:Glial Fibrillary Acidic Protein; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D018832:Molecular Chaperones / Q000494:pharmacology / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D014199:Trehalose / Q000494:pharmacology / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D051272:Glucose Transporter Type 1; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C495678:Slc2a1 protein, mouse; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C528900:glial fibrillary astrocytic protein, mouse; D014199:Trehalose; D014446:Tyrosine 3-Monooxygenase
keywords: Endothelial cells; FT-gel; Parkinson's disease; Trehalose; Tyrosine hydroxylase