Pandanus amaryllifoius Roxb. Leaves Ethanol Extract Ameliorates Lipid and Proinflammatory Cytokines Profiles in a Rat Model of Dyslipidemia.

Objectives: Dyslipidemia has currently become a major health challenge that still opens for safer and more effective modes of treatment. The plant Pandanus amaryllifolius Roxb. (pandan) has been indicated to contain active ingredients that interfere with the pathological pathway of dyslipidemia. The aim of the study was to test the effects of pandan leaves ethanol extract on lipid and proinflammatory profiles in a rat dyslipidemic model. Methods: Dyslipidemia was induced by administration of high-fat feed for 8 weeks. Treatments (vehicle, the reference drug simvastatin at 1.8 mg/kg, and extract at 200, 300 or 600 mg/kg) were given for 4 weeks following the completion of induction. Results: Significant post-treatment decreases in total cholesterol, low density lipoprotein (LDL), and triglyceride levels in groups receiving all doses of extract and simvastatin were observed. Similar results were also found in regards to proinflammatory cytokines levels. Pandan extracts significantly lowered the concentrations of IL-6, TNF-α, and NFκB p65. Characterization of metabolite contents of the extract confirmed the presence of the previously suggested active alkaloids pandamarilactonine-A and B. Conclusion: Taken together, results of the present study implied the ameliorating effects of pandan leaves ethanol extract in dyslipidemic condition which is potential for opening an avenue in combating this essential component of metabolic disorder.

Piperine-hydroxybenzoate as phytochemistry antiosteoarthritis combination: Structural, solubility, and in vivo antiinflammatory study.

This study discusses the composition and structure determination of a new multicomponent system from antiinflammatory natural ingredients, consisting of piperine (Pip) and 4-hydroxybenzoic acid (HBA), named Pip-HBA. In addition, this research studied its solubility and anti-inflammatory activity. After screening the stoichiometric proportions, this multicomponent system formation reaction was carried out using the solvent-dropped grinding and evaporation methods. Characterizations using solid analysis including differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and Fourier transform infrared spectroscopy (FTIR), confirmed the formation of Pip-HBA. These multicomponent systems showed different thermograms and diffractograms. Furthermore, the FTIR spectrum of Pip-HBA multicomponent system differs from the physical mixture and its constituent components. Single crystal diffractometry (SCXRD) determined Pip-HBA to be a new multicomponent system structure in three dimensions. Pip-HBA showed increased solubility and anti-inflammatory activity compared to single piperine. Therefore, Pip-HBA multicomponent system has quite potential for further preparation development.

Decreased Expression of EP3 Receptor mRNA in the Brain of Mouse Model of Autism Spectrum Disorder.

BACKGROUND: Accumulating evidence has implicated the role of neuroinflammation in the pathology of autism spectrum disorder (ASD), a neurodevelopmental disorder. OBJECTIVES: To investigate the expression of prostaglandin EP3 (EP3) receptor mRNA in the brain of ASD mouse model. METHODS: Pregnant mice were injected with valproic acid (VPA) 500 mg/kg intraperitoneally at 12.5 d gestation. The offspring were tested at the age of 5-6 weeks old for their social interaction behavior. Each mouse was assessed for prostaglandin EP3 receptor expression in the prefrontal cortical, hippocampal and cerebellar areas one day after the behavioral test. RESULTS: Compared to the naive, mice born to dams treated with VPA demonstrated a significantly shorter duration of sniffing behavior, a model of social interaction. Results further showed that the expression of EP3 receptor mRNA was significantly lower in all three brain regions of the mice born to VPA-treated dams. CONCLUSION: The present study provides further evidence of the relevance of the arachidonic acid cascade as an essential part of neuroinflammation in the pathology of ASD.

Anti-neuropathic Pain Mechanistic Study on A. conyzoides Essential Oil, Precocene II, Caryophyllene, or Longifolene as Single Agents and in Combination with Pregabalin.

BACKGROUND: Neuropathic pain has become a contributor to the global burden of illness. However, the currently available drugs exhibit inadequate pain relief and significant side effects. Our previous study demonstrated that the essential oil of Ageratum conyzoides exerts potent antineuropathic pain activity through opioid receptor activation. Precocene II, longifolene, and caryophyllene are the largest component of the A. conyzoides essential oil. OBJECTIVE: The objective of the study was to determine the anti-neuropathic pain activity of precocene II, longifolene, and caryophyllene as single agents and in combination with pregabalin. Possible mechanisms of action involving the opioid receptor, ATP-sensitive potassium channel, and gammaaminobutyric acid (GABA) were further investigated. METHODS: The experimental animals (male mice Swiss Webster) were divided randomly into seven groups, namely, Normal control (naïve mice), Negative control (CMC 1%), Sham (CMC 1%), Positive control (Pregabalin 0,195 mg/ 20 g BW of mice), Test I (Precocene II 21.09 mg/Kg BW), Test II (Longifolene 9.94 mg/Kg BW), and Test III (Caryophyllene 3.64 mg/Kg BW). Each group contained 3 animals. The test groups that demonstrated anti-neuropathic pain activity were further tested in combination with pregabalin, followed by mechanistic studies. The negative, positive, and test I-III groups were induced with chronic constriction injury. RESULTS: The results of the study demonstrated that caryophyllene and longifolene, but not precocene II, exerted anti-neuropathic pain activity. The caryophyllene was shown to involve in the activation of opioid receptors and ATP-sensitive potassium channels. It was also reported to increase GABA concentration in the spinal cord. We further found that longifolene exerted its action via opioid receptor activation. The combination of A. conyzoides essential oil, longifolene, or caryophyllene with pregabalin demonstrated additive anti-neuropathic pain activity. CONCLUSION: Taken together, the results of the present study suggested that the A. conyzoides essential oil and caryophyllene have the potential to be developed as novel drugs to treat neuropathic pain.

Effect of the Surfactant Charge on the Characteristics and Anticancer Effects of Docetaxel-loaded Poloxamer Polymeric Micelles.

BACKGROUND: The main problem in the use of docetaxel as a potent chemotherapeutic agent is its solubility. Practically insoluble docetaxel requires a harsh formulation with high surfactant and alcohol concentrations to comply with the product quality. However, this formulation is inconvenient for patients. Polymeric micelles using a biocompatible polymer, poloxamer, seem to be a promising approach to increase the solubility of docetaxel, avoiding the high polysorbate and alcohol contents in the commercial product and yielding similar or better anticancer effects. OBJECTIVE: This study aims to investigate the effects of surfactant with three different charges on the particle size, chemical stability, in vitro drug release and anticancer efficacy of the docetaxelloaded poloxamer-based polymeric micelle formulation. METHODS: The freeze drying method was used to prepare polymeric micelles of docetaxel. Dynamic light scattering was used to determine particle size. The morphology of particles was investigated using a transmission electron microscope. High Pressure Liquid Chromatography was used to measure encapsulation efficiency, drug loading, and percentage of drug released. MTT assay was used to assess the anticancer effect. RESULTS: Nonionic and anionic surfactants tended to increase the particle size, while cationic surfactants had no effect. Furthermore, the addition of cationic surfactant increased the chemical stability of docetaxel. Poloxamer polymeric micelles have sustained drug release, and the addition of a surfactant can increase polymeric micelle drug release. All surfactant charges increased the anticancer efficacy of docetaxel compared to the commercial formulation Taxotere, except for the formulation prepared with an anionic surfactant. CONCLUSION: The charge of the surfactant affects the particle size, chemical stability, drug release and anticancer properties of docetaxel-loaded poloxamer polymeric micelles. Cationic surfactant formulations have shown to be promising, resulting in the most stable and highest anticancer effect.

Potential metabolites of Arecaceae family for the natural anti-osteoarthritis medicine: A review.

Osteoarthritis (OA) is a chronic inflammatory disorder of the joints caused by fluid and cartilage matrix component reduction. This disease results in symptoms of pain, deformity, and limitation of movement. In general, OA is treated with anti-inflammatory drugs and chondroprotection compounds, includes natural nutraceutical ingredients, which are expected to be effective and have minimal side effects. Arecaceae plants are widely spread worldwide, especially in tropical areas. The objective of this review is to collect information about the Arecaceae family as anti-OA agents, with the main study focusing on the primary and secondary metabolites of plants of the Arecaceae family, i.e., sugar palm (Arenga pinnata), nipa palm (Nypa fruticans), palmyra palm (Borassus flabellifer), date palm (Phoenix dactylifera), and betel nut (Areca catechu) have potential as anti-OA agents. The Arecaceae's metabolites that show anti-inflammatory and chondroprotective effects are galactomannan, fatty acids (linoleic and linolenic acids), flavonoids (quercetin, luteolin, isorhamnetin), phenolics (coumaric acid, ferulic acid), polyphenols (epicatechin), and steroids (stigmasterol, campesterol, spirostane). Based on the reports, the Arecaceae family plants become worthy of being explored and developed into natural anti-OA products, such as supplements or nutraceuticals.

Ameliorating Effects of Virgin Coconut Oil (VCO) on Nicotine Dependence and Quality of Life in Smokers.

BACKGROUND: Safer and effective alternatives to manage nicotine dependence are still required. Preliminary studies have shown the potential of virgin coconut oil (VCO) to be used in dependence treatment. OBJECTIVE: to assess the VCO effect administered for 14 days on nicotine dependence and quality of life. METHODS: Forty smoking subjects participated in an open-label, single-center, pre/post-intervention study, and were required to take 15 ml VCO twice daily for 14 days. They were evaluated with the Fagerstrom Test for Nicotine Dependence (FTND) for nicotine dependence intensity and EuroQol-visual analogue scales (EQ VAS) for quality of life. RESULTS: The VCO regimen improved FTND (0.53 points decrease, p<0.05) and EQ-VAS (5.85 points increase p<0.01) scores. Adverse events were all mild. CONCLUSION: Results of the present study suggest that VCO has the potential to be a safe and effective adjunct therapy for the management of nicotine dependence.

Effect of Banana (Musa sp.) Peels Extract in Nanoemulsion Dosage Forms for the Improvement of Memory: In Vitro & In Vivo Studies.

BACKGROUND: Banana (Musa sp.) is a plant rich in phytochemical compounds, especially antioxidants, which are hypothesized to inhibit the activity of acetylcholinesterase, an enzyme associated with Alzheimer's Disease. OBJECTIVE: This research aimed to study nanoemulsion preparations of Kepok banana (KEP-NE) and Tanduk banana (TAN-NE) peel extracts for their activities as antioxidants, acetylcholinesterase as well as tyrosinase inhibitors, and as agents to improve short-term memory. METHODS: Nanoemulsion was prepared using a combination of high shear homogenization and ultrasonication. The antioxidant activity test was carried out using DPPH and ABTS methods. Meanwhile, memory improvement was studied in a mouse model with memory impairment induced by alloxan (120 mg/kg b.w) using the Y-maze apparatus. ELISA performed determination of acetylcholinesterase and tyrosinase inhibition. RESULTS: Characterization of the nanoemulsion was performed to include particle size, antioxidant activity, acetylcholinesterase, and tyrosinase inhibition. The particle size and polydispersity index (PI) of KEP-NE and TAN-NE were 84.2 nm (PI: 0.280) and 94.1 nm (PI: 0.282), respectively. The antioxidant activity of DPPH showed that the respective IC50 values of KEP-NE and TAN-NE were 0.64 µg/mL and 1.97 µg/mL. At the same time, the values with the ABTS method were 1.10 µg/mL and 1.72 µg/mL, respectively. The IC50 of KEP-NE on acetylcholinesterase inhibition was 108.80 µg/mL, and that on tyrosinase inhibition was 251.47 µg/mL. The study of short-term memory in the Y-maze revealed that the groups Kepok peel extracts 100 and 300 mg/kg b.w and KEP-NE 100 and 300 mg/kg b.w significantly (P < 0.05) improved short-term memory. CONCLUSION: This study suggests that the nanoemulsion dosage form of Kepok banana peel extract has antioxidant and acetylcholinesterase inhibition and tyrosinase inhibition activities and could potentially be an adjunct alternative treatment for memory disorders. Modifying the smaller drug particle size contributes to the delivery system. The nanoemulsion can increase pharmacological activity.

Mini-Review of Poloxamer as a Biocompatible Polymer for Advanced Drug Delivery

Abstract Poloxamer is a biocompatible polymer that has already been approved by the US FDA for multiple applications. Poloxamer itself has many grades and functional categories that enable the improvement of both physicochemical and biological properties of drugs. In this minireview, the functional properties of poloxamer for physicochemical modification, such as solubility and stability, and biological response modification, such as neuroprotection, cell apoptosis, efflux pump modification, membrane cell modification, and cellular uptake, are discussed to provide a broader understanding to assist the development of poloxamer-based formulations.

Anti-Neuropathic Pain Activity of Ageratum conyzoides L due to the Essential Oil Components.

BACKGROUND: Neuropathic pain is one of the contributors to the global burdens of illness. At present many patients do not achieve satisfactory pain relief even with synthetic painkillers. Taking this into consideration, it is necessary to search for natural product-derived alternative treatment with confirmed safety and efficacy. Ageratum conyzoides L is a plant often used as an analgesic in Indonesia, however, anti-neuropathic pain activity of this plant is still unknown. OBJECTIVE: To determine the anti-neuropathic pain activity of the essential oil and non-essential oil component (distillation residue) of A. conyzoides L. METHODS: We conducted the separation of the essential oil component from other secondary metabolites through steam distillation. Both components were tested for anti-neuropathic pain activity using chronic constriction injury animal models with thermal hyperalgesia and allodynia tests. The animals were divided into 7 test groups, namely normal, sham, negative, positive (pregabalin at 0.195 mg/20 g BW of mice), essential oil component (100 mg/kg BW), and non-essential oil component (100 mg/kg BW). Naloxone was tested against the most potent anti-neuropathic pain component (essential oil or non-essential oil) to investigate the involvement of opioid receptors. RESULTS: The GC-MS of the essential oil component indicated the presence of 60 compounds. Meanwhile, non-essential oil components include alkaloid, flavonoid, polyphenol, quinone, steroid, and triterpenoid. This non-essential oil component contained a total flavonoid equivalent to 248.89 ppm quercetin. The anti-neuropathic pain activity test showed significantly higher activity of the essential oil component compared to the non-essential oil component and negative groups (p<0.05). Furthermore, the essential oil component showed equal activity to pregabalin (p>0.05). However, this activity was abolished by naloxone, indicating the involvement of the opioid receptor in the action of the essential oil component. CONCLUSION: The essential oil component of A. conyzoides L is a potential novel substance for use as anti-neuropathic pain.

Ameliorating Effects of Four-Week Fiber-Multivitamin Combination Treatment on Low-Density Lipoprotein Cholesterol, Total Cholesterol, and Apolipoprotein B Profiles in Hypercholesterolemic Participants.

Hyperlipidemia is one of the leading causes of death and requires lipid-lowering treatment to reduce morbidity and mortality. Effective and safe alternative and adjunctive therapies could be beneficial for patients with hyperlipidemia. To assess the effect of a fiber-multivitamin combination product on the lipid parameters low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), triglyceride (TG), and apolipoprotein B (Apo B) in patients with hypercholesterolemia, we conducted a double-blind, randomized, parallel-group study. Forty-one out of 50 randomized hypercholesterolemic participants recruited between August 2016 and March 2018 completed the trial. The participants were assigned to receive either test product (treatment group, n = 20) or placebo (placebo group, n = 21) for 4 weeks following a 6-week dietary intervention (based on education from a dietitian) run-in period. The primary outcome was LDL-c levels and the secondary outcomes were HDL-c, TC, TG, and Apo B levels. All of the outcomes were measured at baseline and week 4 after the completion of run-in period. Participants in both groups had similar LDL-c levels (142 ± 15.7 vs. 143 ± 19.3 mg/dL). After 4 weeks of exposure to test product, participants in the treatment group demonstrated a 17.25 ± 22.26 reduction in LDL-c (p < .05 vs. placebo). This improvement in LDL-c was accompanied by amelioration in TC and Apo B levels, without any detrimental effects on HDL and TG concentration. Results of the present study suggest that fiber-vitamin combination has potential to be used as an adjunct therapy for the management of hypercholesterolemia.

Inhibition of Nicotine Dependence by Curcuminoid Is Associated with Reduced Acetylcholinesterase Activity in the Mouse Brain.

Nicotine is a stimulatory component in tobacco that activates the central nervous system reward pathway and causes nicotine dependence. We found that the anti-inflammatory agent, curcuminoid, prevents nicotine dependence and relapse, as assessed by the conditioned placed preference test. Curcuminoid (1, 3.2, and 10 mg·kg-1, oral) dose-dependently inhibited nicotine dependence and enhanced nicotine extinction when administrated 30 min prior to nicotine administration (0.5 mg·kg-1, i.p.) for 7 days. In addition, curcuminoid significantly suppressed the priming effects of nicotine and inhibited acetylcholinesterase (AChE) activity. Taken together, curcuminoid ameliorates nicotine dependence and relapse, in part via the inhibition of the AChE activity in the brain.

Local sustained delivery of bupivacaine HCl from a new castor oil-based nanoemulsion system.

Bupivacaine HCl (1-butyl-2',6'-pipecoloxylidide hydrochloride), an amide local anesthetic compound, is a local anesthetic drug utilized for intraoperative local anesthesia, post-operative analgesia and in the treatment of chronic pain. However, its utility is limited by the relative short duration of analgesia after local administration (approximately 9 h after direct injection) and risk for side effects. This work is aimed to develop a nanoemulsion of bupivacaine HCl with sustained local anesthetics release kinetics for improved pain management, by exhibiting extended analgesic action and providing reduced peak levels in the circulation to minimize side effects. Herein, biodegradable oils were evaluated for use in nanoemulsions to enable sustained release kinetics of bupivacaine HCl. Only with castor oil, a clear and stable nanoemulsion was obtained without the occurrence of phase separation over a period of 3 months. High loading of bupivacaine HCl into the castor oil-based nanoemulsion system was achieved with about 98% entrapment efficiency and the resulting formulation showed high stability under stress conditions (accelerated stability test) regarding changes in visual appearance, drug content, and droplet size. We show herein that the in vitro release and in vivo pharmacokinetic profiles as well as pharmacodynamic outcome (pain relief test) after subcutaneous administration in rats correlate well and clearly demonstrate the prolonged release and extended duration of activity of our novel nanoformulation. In addition, the lower Cmax value achieved in the blood compartment suggests the possibility that the risk for systemic side effects is reduced. We conclude that castor oil-based nanomulsion represents an attractive pain treatment possibility to achieve prolonged local action of bupivacaine HCl.

Evaluation of Rational Drug Use for Acute Pharyngitis Associated with the Incidence and Prevalence of the Disease at Two Community Health Centers in Indonesia.

According to Indonesia's Result of Basic Health Research of 2013, prevalence of acute respiratory infection in 2007 and 2013 were not significantly different (25.5% and 25.0%, respectively). Identifying the cause of acute pharyngitis is a key point in determining the optimal treatment. The main purpose is to evaluate the rational use of drugs and its irrational impact as well as the correlation of the drug use with the incidence and prevalence of acute pharyngitis. This study was a descriptive and observational study, carried out retrospectively and concurrently at two community health centers located in Bandung and Cimahi, Indonesia. There was overprescription of antibiotics in 80.01% of prescription cases, with a total of 8.98% being non-treatment option, and 62.43% being irrational use of corticosteroids. The incidence and prevalence of acute pharyngitis at one health center in Bandung were 2.45% and 2.31%, respectively, with an irrationality rate of 83.82%. Those recorded at one health center in Cimahi were 2.11% incidence and 2.00% prevalence with an irrational rate of 91.29%. It can be concluded that there is still an irrational use of medicines in the treatment of acute pharyngitis in community health centers. The higher incidence and prevalence might indicate the declining quality of health services.

The In Vitro-In Vivo Safety Confirmation of PEG-40 Hydrogenated Castor Oil as a Surfactant for Oral Nanoemulsion Formulation.

Evaluation on the safety use of high concentration of polyoxyl 40 (PEG-40) hydrogenated castor oil as a surfactant for oral nanoemulsion was performed in Webster mice. As previously reported, nearly 20% of PEG-40 hydrogenated castor oil was used to emulsify the glyceryl monooleate (GMO) as an oil to the aqueous phase. Thermodynamically stable and spontaneous nanoemulsion was formed by the presence of co-surfactant polyethylene glycol 400 (PEG-400). Standard parameters were analyzed for nanoemulsion including particle size and particle size distribution, the surface charge of nanoemulsion, and morphology. To ensure the safety of this nanoemulsion, several cell lines were used for cytotoxicity study. In addition, 5000 mg/kg body weight (BW) of the blank nanoemulsion was given orally to Webster mice once a day for 14 days. Several parameters such as gross anatomy, body weight, and main organs histopathology were observed. In particular, by considering the in vivo data, it is suggested that nanoemulsion composed with a high amount of PEG-40 hydrogenated castor oil is acceptable for oral delivery of active compounds.

Cardiovascular effects of Phaleria macrocarpa extracts combined with mainstay FAC regimen for breast cancer.

DLBS1425 is a bioactive compound extracted from Phaleria macrocarpa, with anti-proliferative, anti-inflammatory and anti-angiogenic properties against cancer cells. The present study was aimed to assess cardiotoxicity of DLBS1425, compared to the mainstay regimen for breast cancer, 5-fluorouracil:doxorubicin:cyclophosphamide (FAC, given at 500/50/500 mg/m(2)). Treatment with FAC regimen at standard dose resulted in very severe toxicity, so mice had no chance to survive for more than 7 days following initial drug treatment. Furthermore, histological examination on the heart revealed severe muscular damage when mice were given the FAC regimen alone (severe toxicity). FAC as chemotherapeutic regimen exerted high toxicity profile to the cardiovascular cells in this experiment. Meanwhile, treatment with DLBS1425 alone up to a dose equivalent to as high as 300 mg three times daily in human had no hazardous consequences on the heart, hematological feature, as well as general safety. In the cardiovascular cells, DLBS1425 in the presence of FAC regimen (one-eight of the initial dose) gave protection to the cardiac muscle cells as well as other hematological features. Taken together, results of the present study suggest that DLBS1425 is safe when used as adjuvant therapy for breast cancer and may be even protective against cardiac cellular damage produced by chemotherapeutic regimen.

Intraoral film containing insulin-phospholipid microemulsion: formulation and in vivo hypoglycemic activity study.

Non-invasive administration of insulin is expected for better diabetes mellitus therapy. In this report, we developed intraoral preparation for insulin. Insulin was encapsulated into nanocarrier using self-assembly emulsification process. To increase lipophilicity of insulin, it was dispersed in phospholipid resulted in insulin-phospholipid solid dispersion. The microemulsion formula was established from our previous work which contained glyceryl monooleate (GMO), Tween 20, and polyethylene glycol (PEG 400) in a ratio of 1:8:1. To confirm the formation of insulin-phospholipid solid dispersion, PXRD, FTIR spectroscopy, and Raman spectroscopy were performed. Then, the microemulsion was evaluated for droplet size and distribution, zeta potential, entrapment efficiency, physical stability, and Raman spectroscopy. In addition, microemulsion with expected characteristic was evaluated for in vitro release, in vitro permeation, and in vivo activity. The droplets size of ∼100 nm with narrow distribution and positive charge of +0.56 mV were formed. The insulin encapsulated in the oil droplet was accounted of >90%. Water-soluble chitosan seems to be a promising film matrix polymer which also functioned as insulin release controller. Oral administration of insulin microemulsion to healthy Swiss-Webster mice showed hypoglycemic effect indicating the success of this protein against a harsh environment of the gastrointestinal tract. This effectiveness significantly increased by fourfold as compared to free insulin. Taken together, microemulsion seems to be a promising carrier for oral delivery of insulin.

Suppression of methamphetamine-seeking behavior by nicotinic agonists.

To understand the mechanism of methamphetamine (MAP) craving from the viewpoint of nicotinic acetylcholinergic transmission, we examined the responsible site of the brain for anticraving effects produced by nicotinic agonists by using a MAP self-administration paradigm in rats. Systemic nicotine and an acetylcholinesterase inhibitor, donepezil, attenuated the reinstatement of MAP-seeking behavior by means of the activation of nicotinic acetylcholinergic receptors, but not muscarinic acetylcholinergic receptors, in the nucleus accumbens core, prelimbic cortex, amygdala, and hippocampus. Among these regions, with the exception of the hippocampus, we also found functional differences in this reinstatement. The nicotinic antagonist mecamylamine alone did not reinstate MAP-seeking behavior. These results suggest that the inactivation of nicotinic acetylcholinergic transmission may be an essential factor in the appearance of MAP-seeking behavior, and, thus, the normalization of the inactivated state may result in the suppression of the reinstatement. Our findings also indicate that there are functional differences in the responsible brain subregions. Extending this view to the treatment of MAP dependence, our results suggest that activators of nicotinic acetylcholinergic transmission are possible anticraving agents.

Decrease in prostaglandin level is a prerequisite for the expression of cannabinoid withdrawal: a quasi abstinence approach.

Cannabinoid withdrawal has been indicated in both human and animal subjects. One of pathways proposed to facilitate cannabinoid action is the arachidonic acid cascade. Previously, we have shown that prostaglandin attenuated the expression of withdrawal signs in tetrahydrocannabinol-dependent mice. It follows that the cascade might participate in the expression of cannabinoid withdrawal. We utilized a quasi abstinence approach (the induction of a state of cannabinoid withdrawal without giving any cannabinoid substances in a naïve animal) to describe the relationship between the change in prostaglandin level, an end product of the arachidonic acid cascade, and the expression of cannabinoid withdrawal. Administration of 10 mg/kg diclofenac, a prostaglandin synthesis inhibitor, i.p. 30 min before SR 141716A induced cannabinoid withdrawal signs in naïve mice, which were comparable to the true abstinence in cannabinoid-tolerant mice. In turn, 10 mg/kg Delta(8)-THC i.p., given 15 min prior to SR 141716A, blocked the expression of these signs. These results suggested that the decrease in prostaglandin level is a prerequisite for the expression of cannabinoid withdrawal.

New perspectives in the studies on endocannabinoid and cannabis: a role for the endocannabinoid-arachidonic acid pathway in drug reward and long-lasting relapse to drug taking.

Growing evidence on the involvement of cannabinoids in the rewarding effects of various kinds of drugs of abuse has suggested that not only the classical dopaminergic and opioidergic, but also the most recently established endocannabinoid system is implicated in the brain reward system. Furthermore, the interplay between the three systems has been shown to be an essential neural substrate underlying many aspects of drug addiction including craving and relapse. Relapse, the resumption of drug taking following a period of drug abstinence, is considered the main hurdle in treating drug addiction. Yet, little is known about its underlying mechanisms. The link between the endocannabinoid system and the arachidonic cascade is currently being clarified. While several findings have, indeed, shown the essential role of the endocannabinoid system in the reinstatement model, the endocannabinoid-arachidonic acid pathway may also be an important part in the neural machinery underlying relapse. This evidence may provide an alternative approach that will open a novel strategy in combating drug addiction.