Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model.

Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered a prodromal model of SZ, suitable for studying psychotic conversion. We evaluated the preventive effect of chronic N-acetylcysteine (NAC) administration, covering the prenatal era to adulthood, on the reaction following the Amph challenge, which mimics the outbreak or conversion of psychosis, in adult Het Disc1 mice. Biochemical and morphological features were examined in the striatum of NAC-treated mice. Chronic NAC treatment normalized the Amph-induced activity in the Het Disc1 mice. Furthermore, the striatal phenotypes of Het Disc1 mice were rescued by NAC including dopamine receptors, the expression of GSK3s, MSN dendritic impairments, and striatal PV density. The current study demonstrated a potent preventive effect of chronic NAC treatment in Disc1 Het mice on the acute Amph test, which mimics the outbreak of psychosis. Our findings not only support the benefit of NAC as a dietary supplement for SZ prodromes, but also advance our knowledge of striatal dopamine receptors, PV neurons, and GSK3 signaling pathways as therapeutic targets for treating or preventing the pathogenesis of mental disorders.

miR-200a-3p modulates gene expression in comorbid pain and depression: Molecular implication for central sensitization.

Chronic pain and depression are often comorbid exhibiting common clinical presentations and biological connections related to central nervous system sensitization. Epigenetic regulation of gene expression in the brain plays a crucial role in response to long-lasting stress and chronic pain, and microRNA imbalance in the prefrontal cortex (PFC) might be involved in central sensitization. Male Sprague Dawley rats were subjected to unpredictable chronic mild stress (UCMS) and spared nerve injury (SNI) to initiate depressive-like behavior and chronic pain behavior, respectively. The next-generation sequencing technique was employed to analyze PFC microRNAs in both the UCMS and SNI models. Rats exposed to either UCMS or SNI exhibited both depressive-like and chronic pain behaviors. Five specific microRNAs (miR-10a-5p, miR-182, miR-200a-3p, miR-200b-3p, and miR-429) were simultaneously down-regulated in the depressive-like and chronic pain models after 4 weeks of short-term stress. Gene ontology revealed that the 4-week period of stress enhanced neurogenesis. Only the miR-200a-3p level was continuously elevated under prolonged stress, suggesting roles of reduced neurogenesis, inflammatory activation, disturbed circadian rhythm, lipid metabolism, and insulin secretion in the co-existence of pain and depression. Thus we conclude that miR-200a-3p might be a specific biomarker of central sensitization in chronic pain and depression.

Bupropion for interferon-alpha-induced depression in patients with hepatitis C viral infection: an open-label study.

Interferon (IFN)-α therapy for chronic hepatitis C virus (HCV) infection is frequently associated with major depressive episodes. Bupropion, a commonly used antidepressant agent, has recently found to have strong anti-inflammatory effects in animal models. Despite of the theoretical relevancy, the antidepressant effect of bupropion in IFN-alpha-induced depression has never been studied. Ten HCV patients with IFN-α-induced depression were recruited to receive 8-week bupropion treatment and were assessed every 2 weeks for depressive symptoms by the Hamilton rating scale for depression (HAMD) and somatic symptoms by the Neurotoxicity Rating Scale (NRS). Four of the 10 patients met the criteria for remission (total HAMD scores≤7), and 5 patients met the criteria for response (at least 50% reduction in total HAMD scores). In addition, 5 patients had 50% decreases in NRS for neuropsychiatric symptoms. This preliminary open-label study suggests that bupropion is effective in treating IFN-alpha-induced depressive and somatic symptoms.

Polyunsaturated fatty acids (PUFAs) levels in patients with cardiovascular diseases (CVDs) with and without depression.

BACKGROUND: Cardiovascular diseases (CVDs) are commonly comorbid with depression and vice versa. Polyunsaturated fatty acids (PUFAs) have been suggested to mediate in CVDs and depression in cross-sectional and observational studies. With the patients of CVDs, we investigated the role of depression on the effect of PUFAs. METHODS: Forty-four patients with CVDs were recruited and assessed with Hamilton depression rating scale (HAMD). Patients' CVDs markers were measured by electrocardiogram and their red blood cell (RBC) samples were collected for PUFAs analyses. RESULTS: The data of 44 subjects were analyzed; where 10 participants (23%) with CVDs had moderate or severe depression, defined by a HAMD score more than 19 points. The moderate depression group had lower docosahexaenoic acid (DHA), omega-3 (N3) and omega-6(N6) to N3 (N6/N3) ratio than non-depression group (HAMD score less than 8), while no differences between the 2 groups in terms of corrected QT (QTc) intervals and high sensitivity C-reactive protein (hsCRP) levels. Furthermore, when we analyzed the data with an inclusion of a more heterogeneous depression group, where HAMD score is greater than or equal to 10 (mild depression group, N=24), the differences in PUFAs levels between the 2 groups disappear. Secondary analysis of the moderate depression group showed a positive correlation between DHA, N3 PUFAs, and N6/N3 ratio and total HAMD scores, a positive correlation between N3 PUFAs and QTc intervals in non-depression group. CONCLUSION: Moderate depression group of patients with CVDs had lower levels of DHA, N3, and N6/N3 ratio than non-depression group, while both groups had no differences in QTc and hsCRP. On the other hand, the differences in PUFAs levels disappear in the mild depression group after inclusion of patients with CVDs with greater heterogeneity of depression. Hence, the role of N3 PUFAs is implicated in depression of patients with CVDs if the depression status is more strictly defined.

Methylation and expression patterns of tropomyosin-related kinase genes in different grades of glioma.

Tropomyosin-related kinase family (NTRK1, NTRK2 and NTRK3) is well known to play an important role in the pathogenesis of brain tumour, which exhibit heterogeneity in its biological and clinical behaviour. However, the mechanism that regulates NTRKs in glioma is not well understood. The present study investigates the epigenetic status (methylation) of NTRKs and their expression in different grades of glioma. Promoter methylation and structural relationship of NTRKs was assessed using methylation-specific PCR followed by chromatin immunoprecipitation in brain tissue samples from 220 subjects with different grades of glioma. Control brain samples were also assessed similarly. Reverse transcriptase PCR was performed to analyse the expressions of NTRK mRNAs in the grades of glioma. In addition, the expression level of p75(NTR) protein was analysed using immunofluorescent technique in all of the samples. The overall percentage of NTRK3 gene methylation frequency with subsequent loss of mRNA expression was significantly higher in glioma compared with control samples (p < 0.05). No such significance was observed in other NTRK1 and NTRK2 genes. Further, mRNA expression pattern of NTRK1 and NTRK2 genes was found to be significantly higher in low grades as compared with high grades (HG) and control samples (p < 0.05). Survival rate of HG patients with negative expressions of NTRK1 and NTRK2 was poor than those with the positive expressions of both NTRK1 and NTRK2. Further, a significant correlation was observed with reduced expression of p75(NTR) and the expression pattern of NTRK family in glioma as compared with the control samples (p < 0.05). There exists a correlation between the expression of NTRK family and different grades of glioma with a significant suggestion that the promoter methylation does not play role in the regulation of these genes in glioma. Further, poor survival could be associated with NTRK mRNAs 1 and 2. Hence, NTRKs are potential probes for assessing the behaviour of different grades of glioma, which could also function as significant prognostic factors and thus deserve wider attention for an effective management of the grades.

Frequency variations in the methylated pattern of p73/p21 genes and chromosomal aberrations correlating with different grades of glioma among south Indian population.

Gliomas are the most common primary brain tumors in India. The main epigenetic modification in glioma is aberrant DNA methylation that is now renowned to be a common hallmark of brain tumors. This study was designed to determine the frequency of aberrant CpG island methylation in the promoter regions of p21 and p73 in different grades of glioma and to explore their respective chromosomal aberrations. Total of 160 patients with histologically confirmed grades of glioma (I, II, III, and IV) were included in the study. DNA samples from blood and brain tissues, including benign lesions were subjected to sodium bisulfite conversion and hypermethylation detection using methylation-specific PCR followed by RT-PCR. Western blotting was also carried out for p21 and its related protein, p53. A total of 124 of 160 glioma samples (77.5%) displayed CpG island hypermethylation of both p73, p21 genes associated with the loss of mRNA expression (P < 0.001) and the loss of protein expressions (p53 independent p21 expression). p73 gene showed increased methylation frequency in all grades, 40 of 60 (66%) glioblastomas and 16 of 30 (53.3%) anaplastic astrocytoma, 10 of 20(50%) oligodendrogliomas, 8 of 20 (40%) ependymoma, and low-grade glioma 6 of 20 (30%). The percentage of methylation significantly well correlated with the overall survival and also with chromosomal loss. Thus, the studied glioma patients among south Indians showed a high frequency of aberrant methylation with varied chromosomal signatures in different grades, playing a role in aggressiveness and characterization of a particular grade, the appreciation of which might help for designing a specific therapy.

Biochemical and cytogenetic analysis of brain tissues in different grades of glioma patients.

BACKGROUND: Glioma, a neoplasm of neuroglial cells, is the most common type of brain tumor, constituting more than 50% of all brain tumors. PURPOSE: This report summarizes the current knowledge regarding the clinical utility of biochemical enzyme markers for both diagnostic and therapeutic purposes in different grades of glioma. METHODS: Sixty patients with different grades of glioma include glioblastoma multiforme (n=20), Anaplastic astrocytoma (n=10). Oligodendroglioma (n=10). Ependymoma (n=10), Pilocytic astrocytoma (n=10) and patients with benign lesions (n=5) served as controls. Activity of antioxidants and marker enzymes were assayed in all grades followed by karyotyping. RESULTS: Activities of antioxidant enzymes reduced significantly (p<0.05) compared to controls except CAT, GST that showed marked increase (p<0.05) in accordance with malignancy. CK, Na-K(+) ATPases, 5'-Nucleotidases showed marked increase in grade IV. Similarly, Mg2-ATPase, Ca2+ATPases showed significant increase in grade III. CONCLUSION: The clinical importance for classification and treatment of glioma is governed by biochemical enzyme markers. The study of enzymes supported by related chromosomal changes is anticipated to provide better appreciation of biological properties in different grades of glioma.