Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various classes of antidepressant drugs with distinct pharmacologic actions are differentially effective in the treatment of classic melancholic depression--characterized by pathological hyperarousal and atypical depression--associated with lethargy, hypersomnia, and hyperphagia. All antidepressant agents exert their therapeutic efficacy only after prolonged administration. In situ hybridization histochemistry was used to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of 3 different classes of activating antidepressant drugs which tend to be preferentially effective in treating atypical depressions, on the expression of central nervous system genes thought to be dysregulated in major depression. Daily administration (5 mg/kg, i.p.) of the selective 5-hydroxytryptophan (5-HT) reuptake inhibitor fluoxetine, the selective alpha 2-adrenergic receptor antagonist idazoxan, and the nonspecific monoamine oxidase A and B inhibitor phenelzine increased tyrosine hydroxylase mRNA levels by 70-150% in the locus coeruleus after 2 weeks of drug and by 71-115% after 8 weeks. The 3 drugs decreased corticotropin-releasing hormone mRNA levels by 30-48% in the paraventricular nucleus of the hypothalamus. The decreases occurred at 8 weeks but not at 2 weeks. No consistent change in steroid hormone receptor mRNA levels was seen in the hippocampus with the 3 drugs, but fluoxetine and idazoxan increased the level of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA, respectively, after 8 weeks of drug administration. Proopiomelanocortin (POMC) mRNA levels in the anterior pituitary and plasma adrenocorticotropic-hormone (ACTH) levels were not altered after 2 or 8 weeks of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. 135 83

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by resistance to aldosterone, and the renal form of PHA1 is associated with heterozygous inactivating mutations in NR3C2, which encodes mineralocorticoid receptor (MR). Here we report a case of renal PHA1 due to a novel frameshift mutation in NR3C2. A 10-day-old Japanese male infant, born at 39 weeks gestation (birth weight, 2,946 g), was admitted to our hospital because of lethargy and vomiting, with a 6.7% weight loss since birth. Laboratory test results were: Na+, 132 mEq/L; K+, 6.6 mEq/L; Cl+, 93 mEq/L. Both plasma aldosterone level and plasma renin activity were markedly elevated at diagnosis, 2,940 ng/dL (normal range: 26.9-75.8 ng/dL) and 560 ng/mL/h (normal range 3.66-12.05 ng/mL/h), respectively. Direct sequence analysis of NR3C2 revealed a novel heterozygous mutation (c.3252delC) in the patient and his father. The mutation causes a frameshift starting at amino acid I 963 within the C terminal ligand-binding domain of MR and results in a putative abnormal stop codon at amino acid 994, with an extension of 10 amino acids compared to normal MR. We performed cell culture experiments to determine the levels of mutant NR3C2 mRNA and MR, and evaluate the effects of the mutation on MR response to aldosterone. The mutation decreased the expression of MR, but not NR3C2 mRNA, and led to decreased MR function, with no dominant negative effect. These results provide important information about MR function and NR3C2 mutation in PHA1.
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PMID:A novel frameshift mutation in NR3C2 leads to decreased expression of mineralocorticoid receptor: a family with renal pseudohypoaldosteronism type 1. 2772 60