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Indirubins deplete striatal monoamines in the intact and MPTP-treated mouse brain and block kainate-induced striatal astrogliosis.

Authors
Magiatis-P; Polychronopoulos-P; Skaltsounis-AL; Lozach-O; Meijer-L; Miller-DB; O'Callaghan-JP
Source
Neurotoxicol Teratol 2010 Mar-Apr; 32(2):212-219
NIOSHTIC No.
20036590
Abstract
The indirubins long have been used in Chinese medicine for treatment of myelocytic leukemia. Among the many more recently described biological activities of the indirubins, attention has been directed toward the ability of these compounds to inhibit GSK-3 and CDKs, kinases implicated in neurodegenerative conditions. Little information is available on effects of indirubins on chemically-induced neurodegeneration. Here we examined the influence of three indirubins on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and kainic acid (KA)-induced neurotoxicity in the mouse. The three indirubins examined were 6-bromoindirubin- 3'-oxime (6BIO), 5-bromoindirubin-3'-oxime (5BIO) and 5-amino-6-bromoindirubin (5A6BI). The first two derivatives were previously described indirubins with low nanomolar inhibitory activity against GSK-3 and CDKs. The third compound was synthesized by the dimerization of 5-amino-6-bromoisatin with 3-acetoxyindol. The synthesis of the key compound 5-amino-6-bromoisatin was based on the bromination of the ketal of 5-amino-isatin. All indirubins examined decreased various measures associated with dopaminergic neurotransmission in striatum. These effects occurred alone or over and above the decrements seen following administration of the dopaminergic neurotoxicant, MPTP. Striatal serotonin and serotonin turnover were decreased by the indirubins in MPTP-treated mice. None of these striatal effects of the indirubins alone were associated with evidence of astrogliosis, an indicator of underlying neuropathology, nor did they potentiate the astrogliosis accompanying administration of MPTP. In general, the indirubins reduced KA-associated mortality and striatal but not hippocampal astrogliosis due to this toxicant. The data suggest that indirubins affect striatal biogenic amine levels and turnover in intact mice. The data do not indicate a neuroprotective action of indirubins in mice treated with MPTP but that they do suggest that they may be neuroprotective against KA-induced injury of the neostriatum.
Keywords
Neurotoxic-effects; Neurotoxicity; Neurotoxicology; Neurotoxins; Laboratory-animals; Animals; Animal-studies; Author Keywords: Indirubin; MPTP; Kainate; Astrogliosis; Dopamine; Serotonin
Contact
James P. O'Callaghan, Molecular Neurotoxicology and Chronic Stress & Neurotoxicology Laboratories, Health Effects Laboratory Division, Centers for Disease Control and Prevention-NIOSH, 1095 Willowdale Road, Morgantown, WV 26505, USA
CODEN
NETEEC
CAS No.
51-61-6; 487-79-6; 28289-54-5
Publication Date
20100301
Document Type
Journal Article
Email Address
jdo5@cdc.gov
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Issue of Publication
2
ISSN
0892-0362
NIOSH Division
HELD
Source Name
Neurotoxicology and Teratology
State
WV
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