Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4’-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC

Compulsive-like effects of quinpirole on drinking behavior in rats are inhibited by substituting ethanol for water

We have previously reported that in rats given the choice between operant and free access to water (contrafreeloading: CFL), repeated administrations of quinpirole, a D2/D3 dopamine receptor agonist, shifted the animals towards the operant access and inhibited water intake. The purpose of the present study was to investigate the influence of substituting different concentrations of ethanol (2, 4, 6%) for water on the effects of repeated daily administrations of vehicle or quinpirole (0.5 mg/ka i.p.) in rats that for 6 days were given access to the fluid according to an FR3 schedule of reinforcement and for the following 9 days were given the choice between operant and free access to the fluid. On the first day quinpirole completely suppressed operant behavior, which however progressively increased in the subsequent sessions, approaching control levels by day 6. Ethanol presentation did not alter these effects of quinpirole. When the resource was also freely available, quinpirole produced the expected shift from free to operant access to water (CFL). Substituting ethanol for water resulted in a concentration-related reduction of the over-responding and, consequently, of CFL induced by quinpirole, In vehicle-injected subjects ethanol did not affect responding and only marginally reduced fluid intake. Thus, ethanol appears to prevent perseveration in performing needless instrumental behavior induced by repeated activation of D2/D3 receptors. (c) 2006 Elsevier B.V. All rights reserved

Compulsive-like effects of repeated administration of quinpirole on drinking behavior in rats

We have previously reported that repeated administrations of quinpirole, a D2/D3 dopamine receptor agonist, facilitate instrumental behavior in rats given the choice between operant and free access to water (contrafreeloading: CFL). The goal of the present study was to investigate the effects of repeated daily administrations of quinpirole (0.5 mg/kg i.p.) on the appetitive versus the consummatory component of water-reinforced behavior, under two experimental conditions. Under one condition, the rats were given access to tap water according to an FR3 schedule of reinforcement. Under the second condition, the rats were given the choice between operant and free access to water. Five major findings were obtained. First, acutely quinpirole suppressed operant behavior and, therefore, water intake for at least I h. Second, upon repeated administrations tolerance developed to the suppressant effect of quinpirole on instrumental behavior but only to a lesser extent to the antidipsic effect, dissociating the appetitive from the consummatory components of water-reinforced behavior. Third, in CFL conditions quinpirole induced a progressively larger preference for the operant access. Fourth, even when the rats were given the choice between free access to highly palatable saccharine (0.05 or 0.01%) solutions and operant access to tap water, quinpirole shifted the animals towards the operant access. Fifth, repeated quinpirole produced lasting consequences on drinking behavior, since after rehydration and under drug-free conditions quinpirole-pretreated rats ingested larger amounts of water than control rats. In conclusion, the repeated activation of D2/D3 receptors appears to induce the rats to perseverate in performing needless instrumental behavior. (c) 2006 Elsevier B.V. All rights reserved

The influence of cost manipulation on water contrafreeloading induced by repeated exposure to quinpirole in the rat

RATIONALE: Quinpirole (QNP), a D2/D3 dopaminergic receptor agonist, was found to elicit an apparently antieconomical drinking behavior called contrafreeloading (CFL). The perseverative operant responding observed may represent a compulsive-like behavior prompted by sensitization to the effects of QNP. OBJECTIVES: In the present study, we investigated the effect of different response costs on instrumental behavior and CFL in rats repeatedly treated with QNP (0.5 mg/kg i.p.). Moreover, we studied the consummatory components of ingestive behavior in no-choice paradigms and the role of learned operant conditioning in free drinking. MATERIALS AND METHODS: In experiment 1, rats were trained to perform under three different fixed ratio schedules of reinforcement (FR1, FR3, and FR10) and were given a choice between operant and free access to water. In experiment 2, rats were divided into four groups, each one resembling experiment 1 in one or more features, with no choice available and water consumption measured at an interval of 0-60 min. RESULTS: (a) Increasing FR significantly reduced CFL % in saline -- but not in QNP-injected groups; (b) under free-drinking conditions, QNP caused a progressive hypodipsic effect which was, however, contrasted by maintaining cues formerly contingent on operant access to water; and (c) under CFL conditions QNP-treated rats drank more than under free access conditions. CONCLUSIONS: QNP confers rigidity in responding for water, impeding adaptation to different contingencies for access to the resource. In QNP-treated rats, CFL behavior appears adaptive as far as it allows animals to partially circumvent the hypodipsic effect of the drug

Clomipramine, but not haloperidol or aripiprazole, inhibits quinpirole-induced water contrafreeloading, a putative animal model of compulsive behavior.

Rationale: Repeated administrations of the D2/D3 agonist quinpirole (QNP) to rats elicit an antieconomical pattern of drinking called " contrafreeloading" (CFL), a putative model of compulsive-like behavior. Objectives: We tested the sensitivity of QNP-induced CFL to haloperidol (HAL), aripiprazole (ARI), and clomipramine (CIM), the latter proven effective in the treatment of obsessive-compulsive disorder (OCD). Methods: Rats were trained under a schedule of reinforcement (FR3) for water. On days 1-6, water was only available through lever pressing. On days 7-15, a choice between operant and free access was provided. QNP 0.5 mg/kg was administered alone or in combination with HAL (0.1 or 0.2 mg/kg), ARI (0.3 or 1 mg/kg), or CIM (5 or 10 mg/kg). Results: Acutely QNP suppressed operant behavior and, therefore, water intake; upon repeated administrations, tolerance developed to this suppressant effect on responding but only to a lesser extent to the antidipsic effect. In choice conditions, QNP induced a progressive preference for the operant access (CFL). HAL per se, but not CIM and ARI, significantly reduced both responding and drinking (operant phase). In the choice phase, HAL and CIM inhibited CFL, but only the latter reinstated total water intake. ARI, in combination with QNP, increased responding. Conclusions: CIM reinstates control patterns of drinking, while HAL and ARI where partially or not effective at all, respectively. As far as CIM is considered a first line treatment in OCD, these results further strengthen the notion that QNP-induced CFL belongs to the realm of dopaminergic drug-induced compulsive behaviors. © 2011 Springer-Verlag

176. Viper envenomation with ocular neurotocic effects managed without antidote admiistration:a case report 39th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 21-24 May 2019, Naples, Italy

Along with the more common clinical features, European viper envenomations may rarely present with neurotoxic manifestations. Those include muscle weakness, drowsiness, paresthesia, dyspnea and ocular complaints among others. Ocular neurotoxicity as an indication for antidote administration is still debated In this case the management with supportive/symptomatic treatment was sufficient. CASE REPORT. In May 2018, a 19-­‐year old man was admitted to an external emergency unit 20 minutes after a viper bite on the proximal phalanges of the right hand. The Poison Control Centre (PCC) of Policlinico Umberto I Hospital – Sapienza University of Rome was contacted immediately. Local signs of envenomation with fang marks, and swelling of the hand were present. Initial lab work showed no abnormalities. In the following 2 hours edema extended to the middle forearm (Figure 1), and one episode of vomiting was registered. The patient was hydrated and analgesics administered. Four hours post-­‐bite, edema did not progress proximally, but weakness, vertigo and mild abdominal pain were reported. LeuKocytosis (17.0 × 109/L, 90% neutrophils) and increased creatinkinase (245 U/L) were present. The PCC provided two vials of Viper Venom Antitoxin (Biomed) with no indication to administer at this time, but to closely monitor patient for any systemic and neurological manifestations. Seven hours post-­ bite,the swelling was stable, abdominal pain and previous neurological symptomsm regressed, and left ptosis appeared. Laboratory exams showed persistence of leukocytosis (16.6 × 109/l), glucose 123 mg/dL and creatinkinase 216 U/L. The PCC recommended further monitoring. Eighteen hours post-­‐bite ptosis ameliorated, no systemic signs had developed. The patient was discharged 40 hours post-­‐bite with no ptosis, edema in regression and leucocytes towards normalization. This case report suggests the following observations: i) as previously reported, neurological manifestations due to neurotoxins in some viper species venom may be characterized by delayed onset (up to 24 hours, 4-­‐7 hours in this case), association with mild local effects and reversibility; ii) weakness and vertigo preceded the ocular signs, and resolved in about 3 hours; iii) symptomatic management and close monitoring might be the best approach in such cases, with antitoxin recommended as soon as rapid edema extension and/or severe systemic/neurological symptoms appear

Targeting Chemokines and Chemokine GPCRs to Enhance Strong Opioid Efficacy in Neuropathic Pain

Neuropathic pain (NP) originates from an injury or disease of the somatosensory nervous system. This heterogeneous origin and the possible association with other pathologies make the management of NP a real challenge. To date, there are no satisfactory treatments for this type of chronic pain. Even strong opioids, the gold-standard analgesics for nociceptive and cancer pain, display low efficacy and the paradoxical ability to exacerbate pain sensitivity in NP patients. Mounting evidence suggests that chemokine upregulation may be a common mechanism driving NP pathophysiology and chronic opioid use-related consequences (analgesic tolerance and hyperalgesia). Here, we first review preclinical studies on the role of chemokines and chemokine receptors in the development and maintenance of NP. Second, we examine the change in chemokine expression following chronic opioid use and the crosstalk between chemokine and opioid receptors. Then, we examine the effects of inhibiting specific chemokines or chemokine receptors as a strategy to increase opioid efficacy in NP. We conclude that strong opioids, along with drugs that block specific chemokine/chemokine receptor axis, might be the right compromise for a favorable risk/benefit ratio in NP management