Antidiarrheal and Cardio-Depressant Effects of Himalaiella heteromalla (D.Don) Raab-Straube: In Vitro, In Vivo, and In Silico Studies

Himalaiella heteromalla (D.Don) Raab-Straube is a commonly used remedy against various diseases. Crude extract and fractions of H. heteromalla were investigated for a gastrointestinal, bronchodilator, cardiovascular, and anti-inflammatory activities. H. heteromalla crude extract (Hh.Cr) relaxed spontaneous contractions and K+ (80 mM)-induced contraction in jejunum tissue dose-dependently. The relaxation of K+ (80 mM) indicates the presence of Ca++ channel blocking (CCB) effect, which was further confirmed by constructing calcium response curves (CRCs) as they caused rightward parallel shift of CRCs in a manner comparable to verapamil, so the spasmolytic effect of Hh.Cr was due to its CCB activity. Application of Hh.Cr on CCh (1 µM) and K+ (80 mM)-induced contraction in tracheal preparation resulted in complete relaxation, showing its bronchodilator effect mediated through Ca++ channels and cholinergic antagonist activity. Application of Hh.Cr on aortic preparations exhibited vasorelaxant activity through angiotensin and α-adrenergic receptors blockage. It also showed the cardio suppressant effect with negative chronotropic and inotropic response in paired atrium preparation. Similar effects were observed in in vivo models, i.e., decreased propulsive movement, wet feces, and inhibition of edema formation.

The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats

BackgroundThe neuropeptide oxytocin has emerged as a promising pharmacotherapy for methamphetamine (METH) addiction, and clinical trials of intranasal oxytocin are underway. However, there is debate as to how peripherally administered oxytocin alters brain signaling to modulate addiction processes. Interestingly, there is evidence for functional interactions between peripheral oxytocin administration and the vagus nerve. Therefore, this study investigated whether the effects of peripherally administered oxytocin require vagal signaling to reduce METH self-administration and reinstatement of METH-seeking behaviours.MethodsMale and female Sprague-Dawley rats underwent surgery for jugular catheterization and either subdiaphragmatic vagotomy (SDV) or a sham operation. Rats were trained to self-administer METH, and the effect of peripherally administered oxytocin on METH intake was assessed. Rats then underwent extinction, and effects of oxytocin were assessed on cue- and METH-induced reinstatement of METH-seeking.ResultsOxytocin treatment robustly attenuated METH intake in both sexes. Strikingly, SDV entirely prevented the suppressant effect of oxytocin (0.3 mg/kg) on METH intake, and partially prevented the effects of 1 mg/kg oxytocin in both sexes. After extinction, SDV impaired the suppressing effects of oxytocin on cue- and METH-primed reinstatement in males, but not females. SDV was functionally confirmed by measuring food intake following administration of the vagal dependent peptide, cholecyostokin-8.ConclusionOur data suggest that vagus nerve signaling is required for the anti-addiction effects of peripherally administered oxytocin, and that this vagal dependency is partially mediated by sex and drug withdrawal. This study has considerable implications for the applicability of oxytocin as a therapy for METH use disorder for both sexes.

Total and Ionized Calcium and Magnesium Are Significantly Lowered in Drug-Naïve Depressed Patients: Effects of Antidepressants and Associations with Immune Activation

Major depressive disorder (MDD) is associated with changes in the levels of the cations calcium (Ca) and magnesium (Mg) as well as circulating pro- and anti-inflammatory cytokines. The immune-inflammatory nature of MDD has encouraged researchers to use anti-inflammatory drugs as an adjuvant treatment for MDD. However, the effect of this treatment on cation levels has not been studied. The present study examined a) differences in both cations between drug-naïve MDD patients and controls, and b) the effects of a combination of sertraline and ketoprofen, an anti-inflammatory drug, on Ca and Mg (both total and ionized). In the same patients we also examined the associations between both cations and IL-1β, IL-4, IL-6, IL-18, IFN-γ, TGF-β1, zinc and indoleamine 2,3-dioxygenase (IDO). Clinical improvement was estimated using the Beck Depression Inventory-II (BDI-II) at baseline and after follow up for two months. Serum Ca and Mg (total and ionized) were significantly lower in MDD patients as compared with controls, while treatment significantly increased calcium but decreased magnesium levels. There were significant and inverse correlations between the BDI-II scores from baseline to endpoint and Ca (both total and ionized), but not Mg, levels. The effects of calcium on the BDI-II score remained significant after considering the effects of zinc, IDO and an immune activation z unit weighted composite score based on the sum of all cytokines. There was a significant and inverse association between this immune activation index and calcium levels from baseline to endpoint. In conclusion, reduced levels of both cations play a role in the pathophysiology of major depression. Increased calcium levels are coupled to the clinical efficacy of antidepressants and attenuation of immune activation. The suppressant effect of antidepressants on Mg levels may be a side effect of those drugs. New antidepressant treatments should be developed that increase the levels both Ca and Mg.

The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT3 receptor antagonism

The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT3 receptor agonist, SR57227 or the selective 5-HT1A receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT3 receptor antagonism of vortioxetine in association with its reduced SERT occupancy.

Comparison between Sevoflurane/Remifentanil and Propofol/Remifentanil Anaesthesia in Providing Conditions for Somatosensory Evoked Potential Monitoring during Scoliosis Corrective Surgery

Somatosensory evoked potential (SSEP) monitoring is an important tool in spinal corrective surgery. Anaesthesia has a significant influence on SSEP monitoring and a technique which has the least and shortest suppressant effect on SSEP while facilitating a fast recovery from anaesthesia is ideal. We compared the effect of sevoflurane/remifentanil and propofol/remifentanil anaesthesia on SSEPs during scoliosis corrective surgery and assessed patients’ clinical recovery profiles. Twenty patients with idiopathic scoliosis receiving surgical correction with intraoperative SSEP monitoring were prospectively randomised to receive sevoflurane/remifentanil anaesthesia or propofol/remifentanil anaesthesia. During surgery, changes in anaesthesia dose and physiological variables were recorded, while SSEP was continuously monitored. A simulated ‘wake-up’ test was performed postoperatively to assess speed and quality of recovery from anaesthesia. The effects of propofol and sevoflurane resulted in SSEP amplitude variability between 18.0% ± 3.5% to 28.7% ± 5.9% and SSEP latency variability within 1.3% ± 0.4% to 2.6% ± 1.2%. Patients receiving sevoflurane had faster suppression and faster recovery of SSEP amplitude compared to propofol (P <0.05), although propofol anaesthesia showed less within-patient variability in Cz amplitude and latency (P <0.05). On cessation of anaesthesia, time to eye-opening (5.2 vs. 16.5 minutes) and toe movement (5.4 vs. 17.4 minutes) was shorter following sevoflurane (all P <0.05). These findings indicate that propofol produces a better SSEP signal than sevoflurane. However, adjustments in sevoflurane concentration result in faster changes in the SSEP signal than propofol. Assessment of neurological function was facilitated more rapidly after sevoflurane anaesthesia.

Nitrooxyethylation Reverses the Healing-Suppressant Effect of Ibuprofen

Nonsteroidal antiinflammatory drugs like ibuprofen impede tissue repair by virtue of retarding inflammation. The present study was undertaken to explore if linking of nitrooxyethyl ester to ibuprofen reverses its healing-depressant propensity. Nitrooxyethyl ester of ibuprofen (NOE-Ibu) was synthesized in our laboratory through a well-established synthetic pathway. NOE-Ibu was screened for its influence on collagenation, wound contraction and epithelialization phases of healing, and scar size of healed wound in three wound models, namely, incision, dead space, and excision wounds. Besides, its influence on the oxidative stress (levels of GSH and TBARS) was also determined in 10-day-old granulation tissue. NOE-Ibu was further screened for its antiinflammatory activity in rat paw edema model. NOE-Ibu promoted collagenation (increase in breaking strength, granulation weight, and collagen content), wound contraction and epithelialization phases of healing. NOE-Ibu also showed a significant antioxidant effect in 10-day-old granulation tissue as compared to ibuprofen. Results vindicate that the esterification of ibuprofen with nitrooxyethyl group reverses the healing-suppressant effect of ibuprofen. The compound also showed equipotent antiinflammatory activity as ibuprofen.