tretinoin and Basal-Ganglia-Diseases

Lesch-Nyhan disease (LND), caused by complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT), is characterized by a neurological deficit, the etiology of which is unknown. Evidence has accumulated indicating that it might be related to dysfunction of the basal ganglia with a prominent loss of striatal dopamine fibers. Guanine nucleotide depletion has been shown to occur in cells from Lesch-Nyhan patients. In this study we demonstrate that chronic guanine nucleotide depletion induced by inhibition of inosine monophosphate dehydrogenase with low levels (50 nM) of mycophenolic acid (MPA) lead human neuroblastoma cell lines to differentiate toward the neuronal phenotype. The MPA-induced morphological changes were more evident in the dopaminergic line LAN5, than in the cholinergic line IMR32. MPA-induced differentiation, unlike that induced by retinoic acid, caused a less extensive neurite outgrowth and branching (similar to that observed in cultured HPRT-deficient dopaminergic neurons) and involved up-regulation of p53, p21 and bax, and bcl-2 down-regulation without p27 protein accumulation. These results suggest that guanine nucleotide depletion following HPRT deficiency, might lead to earlier and abnormal brain development mainly affecting the basal ganglia, displaying the highest HPRT activity, and could be responsible for the specific neurobehavioral features of LND.

Topics: Basal Ganglia; Basal Ganglia Diseases; Cell Cycle Proteins; Cell Differentiation; Cell Enlargement; Cell Line; Enzyme Inhibitors; Guanine Nucleotides; Humans; Hypoxanthine Phosphoribosyltransferase; IMP Dehydrogenase; Lesch-Nyhan Syndrome; Models, Neurological; Mycophenolic Acid; Neurites; Neuroblastoma; Neurofilament Proteins; Tretinoin; Up-Regulation

Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. We have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacological approaches, we investigated the role of NGFI-B and retinoids in acute behavioral and biochemical responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D(2)/D(3) antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D(1) agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addition, we demonstrate that haloperidol enhances colocalization of NGFI-B and RXRgamma1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. Our data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the molecular cascade induced by neuroleptic drugs.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Antipsychotic Agents; Autoradiography; Basal Ganglia Diseases; Behavior, Animal; Binding Sites; Catalepsy; Corpus Striatum; DNA-Binding Proteins; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Gene Expression Regulation; Haloperidol; In Situ Hybridization; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides; Nuclear Receptor Subfamily 4, Group A, Member 1; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Receptors, Steroid; Retinoid X Receptors; Retinoids; RNA, Messenger; Time Factors; Transcription Factors; Tretinoin