Combination of Niclosamide and Pirfenidone Alleviates Pulmonary Fibrosis by Inhibiting Oxidative Stress and MAPK/Nf-κB and STATs Regulated Genes.

The pathogenesis of pulmonary fibrosis (PF) is extremely complex and involves numerous intersecting pathways. The successful management of PF may require combining multiple agents. There is a growing body of evidence that suggests the potential benefits of niclosamide (NCL), an FDA-approved anthelminthic drug, in targeting different fibrogenesis molecules. This study aimed at investigating the anti-fibrotic potential of NCL alone and in combination with pirfenidone (PRF), an approved drug for PF, in a bleomycin (BLM) induced PF experimental model. PF was induced in rats by intratracheal BLM administration. The effect of NCL and PRF individually and in combination on different histological and biochemical parameters of fibrosis was investigated. Results revealed that NCL and PRF individually and in combination alleviated the histopathological changes, extracellular matrix deposition and myofibroblastic activation induced by BLM. NCL and PRF either individually or in combination inhibited the oxidative stress and subsequent pathways. They modulated the process of fibrogenesis by inhibiting MAPK/NF-κB and downstream cytokines. They inhibited STATs and downstream survival-related genes including BCL-2, VEGF, HIF-α and IL-6. Combining both drugs showed significant improvement in the tested markers in comparison to the monotherapy. NCL, therefore, has a potential synergistic effect with PRF in reducing the severity of PF.

Effect of psychotropic drugs on cortical excitability of patients with major depressive disorders: A transcranial magnetic stimulation study.

Transcranial magnetic stimulation (TMS) can be used to evaluate the effects of pharmacological interventions. The aim of this study was to assess the impact of the selective serotonin reuptake inhibitor, sertraline, and the atypical antipsychotic drugs quetiapine and olanzapine, on cortical excitability in unmedicated patients with major depressive disorder (MDD). The study included 45 medication-free MDD patients diagnosed according to DSM V. They were divided randomly into three groups who received a single oral dose of one of the three drugs sertraline (50 mg), quetiapine (100 mg) and olanzapine (10 mg). Psychological evaluation was conducted using the Mini-Mental State Examination (MMSE) and Beck Depression Inventory Scale (BDI). Resting and active motor thresholds (rMT and aMT) together with contralateral and ipsilateral cortical silent periods (cSP, and iSP) were measured for each participant before and at the time of maximum concentration of drug intake. There was significant increase in excitability of motor cortex after sertraline without changes in GABAB neurotransmission. Quetiapine and olanzapine potentiated inhibitory GABAB neurotransmission (prolongation of cSP); olanzapine additionally prolonged the iSP. Thus TMS can differentiate between the impact of different psychotropic drugs on excitatory and inhibitory transmission in motor cortex.

Global cortical hypoexcitability of the dominant hemisphere in major depressive disorder: A transcranial magnetic stimulation study.

BACKGROUND: Accumulating evidence suggests that major depressive disorders (MDD) are associated with an imbalance of excitation-inhibition within the prefrontal cortex (PFC), generated by a deficit of inhibitory synaptic transmission onto glutamatergic principal neurons. Transcranial magnetic stimulation (TMS) protocols can be used to measure neuronal excitability and GABAergic inhibition and thus provide additional evidence to evaluate this theory. OBJECTIVE: In the present study, TMS protocols were used to compare GABAergic function and cortical excitability of dominant hemisphere in unmedicated patients with MDD versus a control group of healthy individuals. METHODS: The study included 43 MDD patients according to DSM-V and 20 age- and sex- matched healthy volunteers. Psychological evaluation was conducted using the Beck Depression Inventory (BDI). Resting and active motor thresholds (rMT and aMT) together with contralateral and ipsilateral cortical silent periods (cSP, and iSP) were measured for each participant. RESULTS: rMT and aMT were higher in MDD patients compared with the control group, while cSP and iSP were significantly shorter in duration. There were significant positive correlations between the BDI score and rMT, aMT (P=0.001 and 0.002 respectively), and a negative correlation with cSP duration (P=0.001). CONCLUSION: Global hypoexcitability of both pyramidal cortical neurons (elevated MTs) and GABAergic controls (shortened SPs) was evidenced within the left/dominant motor cortex in MDD. These results are consistent with previous reports of abnormal glutamate and GABA function in frontal cortex.