| 1 | Peptides 2003 Jan 24: 137-46 |
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| PMID | 12576095 |
| Title | PLG regulates hnRNP-L expression in the rat striatum and pre-frontal cortex: identification by ddPCR. |
| Abstract | Central dopaminergic systems are implicated in schizophrenia and Parkinson's disease, and are known to be modulated by the endogenous tripeptide Pro-Leu-Gly-NH(2) (PLG or MIF-1, melanocyte-stimulating hormone release inhibiting factor-1). Differential display polymerase chain reaction (ddPCR) was utilized to identify genes that are regulated by protracted PLG treatment (20 mg/kg, i.p. for 28 days) in male Sprague-Dawley rats. A total of 2400 genes were screened and 3 down-regulated bands were identified in the PLG-treated samples. Sequencing analysis revealed a total of six unique cDNA species. One fragment possessed a high degree of homology with Mus musculus hnRNP-L (protein L) mRNA (GenBank #AB009392) (termed PRG1: PLG regulated gene 1). Elongation of the PRG1 cDNA, by RACE-PCR, provided an 835 bp sequence with 95% homology to AB009392 over a 743 bp span. Open reading frame analysis provided a putative amino acid sequence consistent with the identity of PRG1 as rat hnRNP-L. Northern hybridization experiments with PRG1 revealed a 2.3 kb mRNA species that was decreased by 65% in the PLG-treated tissue. Western blot analysis revealed significantly decreased hnRNP-L levels in the striatum and pre-frontal cortex (but not the nucleus accumbens) by 71 and 61%, respectively of PLG-treated animals. The identification of altered expression of hnRNP-L following PLG treatment provides insight into the long-term effects of PLG and may provide insight into its molecular mechanism of action. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Psychiatry Res 2006 Sep 144: 39-47 |
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| PMID | 16916546 |
| Title | Investigating disease susceptibility and the negative correlation of schizophrenia and rheumatoid arthritis focusing on MIF and CD14 gene polymorphisms. |
| Abstract | schizophrenia and rheumatoid arthritis (RA) are both chronic diseases with an estimated genetic component of 60%. While RA is a well-known autoimmune inflammatory joint disease, recent data point to an active immune process also being involved in schizophrenia. Several studies confirmed the negative association between schizophrenia and RA, indicating genetic factors that predispose to the one disorder, while protecting from the other. Macrophage migration inhibitory factor (MIF) and the monocytes surface receptor CD14 are involved in the development and maintenance of chronic inflammation. We therefore investigated if the -G173C single nucleotide polymorphism (SNP) and the tetranucleotide repeat CATT (5 - 8) at position -794 of the MIF gene and the CD14 - C159T transition are candidates for genetic liability to schizophrenia and RA or could explain the negative association between them. In our study 157 schizophrenic patients, 119 patients suffering from RA, and 225 healthy individuals were genotyped. All subjects were Caucasians. The CD14- and MIF-genotypes were equally distributed in all three groups. From our results, we cannot confirm the hypothesis that the investigated genetic mutations within the MIF and/or the CD14 gene are involved in the aetiology of either disease or could explain the negative correlation of schizophrenia and RA. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Psychiatry Res 2006 Sep 144: 39-47 |
|---|
| PMID | 16916546 |
| Title | Investigating disease susceptibility and the negative correlation of schizophrenia and rheumatoid arthritis focusing on MIF and CD14 gene polymorphisms. |
| Abstract | schizophrenia and rheumatoid arthritis (RA) are both chronic diseases with an estimated genetic component of 60%. While RA is a well-known autoimmune inflammatory joint disease, recent data point to an active immune process also being involved in schizophrenia. Several studies confirmed the negative association between schizophrenia and RA, indicating genetic factors that predispose to the one disorder, while protecting from the other. Macrophage migration inhibitory factor (MIF) and the monocytes surface receptor CD14 are involved in the development and maintenance of chronic inflammation. We therefore investigated if the -G173C single nucleotide polymorphism (SNP) and the tetranucleotide repeat CATT (5 - 8) at position -794 of the MIF gene and the CD14 - C159T transition are candidates for genetic liability to schizophrenia and RA or could explain the negative association between them. In our study 157 schizophrenic patients, 119 patients suffering from RA, and 225 healthy individuals were genotyped. All subjects were Caucasians. The CD14- and MIF-genotypes were equally distributed in all three groups. From our results, we cannot confirm the hypothesis that the investigated genetic mutations within the MIF and/or the CD14 gene are involved in the aetiology of either disease or could explain the negative correlation of schizophrenia and RA. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Peptides 2013 Apr 42: 89-96 |
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| PMID | 23416534 |
| Title | Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic, PAOPA: examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia. |
| Abstract | schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |