Molecular Consequences of Depression Treatment: A Potential In Vitro Mechanism for Antidepressants-Induced Reprotoxic Side Effects

The incidence of depression among humans is growing worldwide, and so is the use of antidepressants. However, our fundamental understanding regarding the mechanisms by which these drugs function and their off-target effects against human sexuality remains poorly defined. The present study aimed to determine their differential toxicity on mouse spermatogenic cells and provide mechanistic data of cell-specific response to antidepressant and neuroleptic drug treatment. To directly test reprotoxicity, the spermatogenic cells (GC-1 spg and GC-2 spd cells) were incubated for 48 and 96 h with amitriptyline (hydrochloride) (AMI), escitalopram (ESC), fluoxetine (hydrochloride) (FLU), imipramine (hydrochloride) (IMI), mirtazapine (MIR), olanzapine (OLZ), reboxetine (mesylate) (REB), and venlafaxine (hydrochloride) (VEN), and several cellular and biochemical features were assessed. Obtained results reveal that all investigated substances showed considerable reprotoxic potency leading to micronuclei formation, which, in turn, resulted in upregulation of telomeric binding factor (TRF1/TRF2) protein expression. The TRF-based response was strictly dependent on p53/p21 signaling and was followed by irreversible G2/M cell cycle arrest and finally initiation of apoptotic cell death. In conclusion, our findings suggest that antidepressants promote a telomere-focused DNA damage response in germ cell lines, which broadens the established view of antidepressants’ and neuroleptic drugs’ toxicity and points to the need for further research in this topic with the use of in vivo models and human samples.

A case of delayed-onset multiple oculogyric crisis and torticollis episodes after low dose intramuscular haloperidol in a non-neuroleptic drug overdose setting

This report documents a rare case of delayed-onset multiple acute dystonias after treatment with low dose intramuscular (IM) haloperidol lactate injection in a setting of non-neuroleptic drug overdose. The drug–drug interactions between haloperidol and high levels of paracetamol and naproxen are deliberated upon. A 25-year-old Asian female was admitted after an intentional overdose of medications (paracetamol, naproxen and pregabalin). She received 5 mg of IM haloperidol injection for agitation. 21 hours later she experienced mild intermittent ocular deviation in an upward and outward direction and generalised stiffness, which were self-resolving. An hour later, she required another 2.5 mg of IM haloperidol injection for further agitation. In the 35 hours following her first IM haloperidol (13 hours after the second IM haloperidol), she developed a total of three episodes of oculogyric crisis (OGC) with torticollis. Each episode was treated promptly with IM diphenhydramine 25 mg, and there was remission of symptoms within 15 minutes of treatment. An objective causality assessment revealed a definite relationship between the episodes of acute dystonia with IM haloperidol therapy. Where oral alternatives and IM atypical antipsychotics/benzodiazepines are unavailable, rapid tranquillisation with a high-potency typical antipsychotic is a possibility. However, consideration should be made to combine haloperidol with an anticholinergic agent as prophylaxis against acute dystonia, especially in the setting of drug overdose, even if it is that of a non-neuroleptic drug (in this case, paracetamol and naproxen).

Isolation and Characterization of Anti Psychotic Compound From Cassia Occidentalis Leaf

The aim of the current work was mainly to find the neuroleptic effects of responsible compounds isolated from Cassia occidentalis leaves, on condiontioning avoidance and catalepsy induced psychotic wistar rats. Psychosis was induced by condiontioning avoidance and catalepsy induced in albino wistar rats. An isolated fraction of the ethanolic extract of Cassia occidentalis was ingested orally at 100 mg/kg, p.o dose. Haloperidol was considered as standard neuroleptic drug (10 mg/kg, p.o.). The isolated fractions from the column chromatography showing for the higher neuroleptic activity that facilitated for isolating the pure constituent, that was named trivially as name CO- 1.Precise analysis of the previous investigations with Ethanolic extract of Cassia occidentalis (ETCO) have encouraged us to isolate anti-psychotic responsible consituents from the leaves of Cassia occidentalis for managing the anti-psychotic activity. Collected pooled fractions were subjected to anti-psychotic activity in conditioning avoidance and catalepsy induced wistar rats. The fraction F from ETCO showed strong neuroleptic activity when compared with the commercial standard drug Haloperidol. To propose the constituents that possess anti psychotic activity related to F respectively. Besides, column chromatography analysis was performed with ‘F’ using different solvents and the isolated compound which is named as CO-1. This amorphous powder was extracted from the column with decomposition point. CO-1 is a phenolic compound that was confirmed by IR, Mass Spectrum and NMR analysis.

Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy

Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC50 (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.

Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors

SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.