A novel tramadol-polycaprolactone implant could palliate heroin conditioned place preference and withdrawal in rats: behavioral and neurochemical study.

Drug dependence is a chronic brain disease characterized by craving and recurrent episodes of relapse. Tramadol HCl is a promising agent for withdrawal symptoms management, considering its relatively low abuse potential and safety. Oral administration, however, is not preferred in abstinence maintenance programs. Introducing an implantable, long-lasting formula is suggested to help outpatient abstinence programs achieve higher rates of treatment continuation. Tramadol implants (T350 and T650) were prepared on polycaprolactone polymer ribbons by the wet method. Male Wistar rats were adapted to heroin-conditioned place preference (CPP) at escalating doses (3-30 mg/kg, intraperitoneally, for 14 days). Implants were surgically implanted in the back skin of rats. After 14 days, the CPP score was recorded. Naloxone (1 mg/kg, intraperitoneally) was used to induce withdrawal on day 15, and symptoms were scored. Elevated plus maze and open field tests were performed for anxiety-related symptoms. Striata were analyzed for neurochemical changes reflected in dopamine, 3,4-dihydroxyphenyl acetic acid, gamma-aminobutyric acid, and serotonin levels. Brain oxidative changes including glutathione and lipid peroxides were assessed. The tramadol implants (T350 and T650) reduced heroin CPP and limited naloxone-induced withdrawal symptoms. The striata showed increased levels of 3,4-dihydroxyphenyl acetic acid, and serotonin and decreased levels of gamma-aminobutyric acid and dopamine after heroin withdrawal induction, which were reversed after implanting T350 and T650. Implants restore the brain oxidative state. Nonsignificant low naloxone-induced withdrawal score after the implant was used in naive subjects indicating low abuse potential of the implants. The presented tramadol implants were effective at diminishing heroin CPP and withdrawal in rats, suggesting further investigations for application in the management of opioid withdrawal.

Plant-mediated green synthesis of gold nanoparticles using an aqueous extract of Passiflora ligularis, optimization, characterizations, and their neuroprotective effect on propionic acid-induced autism in Wistar rats.

The current study was conducted to examine an innovative method for synthesizing gold nanoparticles (AuNPs) from an aqueous sweet granadilla (Passiflora ligularis Juss) P. ligularis. Furthermore, the synthesized AuNPs were used to explore their potential neuroprotective impact against propionic acid (PPA)-induced autism. A sweet granadilla extract was used to achieve the synthesis of AuNPs. The structural and dimensional dispersion of AuNPs were confirmed by different techniques, including UV-Vis spectrophotometer (UV-Vis), X-ray Diffraction (XRD) Pattern, Energy Dispersive X-ray (EDX), Zeta potential, and High-Resolution Transmission Electron Microscopy (HRTEM) analysis. The AuNPs mediated by P. ligularis adopt a spherical shape morphology and the particle size was distributed in the range of 8.43-13 nm without aggregation. Moreover, in vivo, the anti-autistic effects of AuNPs administration were higher than those of P. ligularis extract per second. In addition, the reduced anxiety and neurobehavioral deficits of AuNPs were observed in autistic rats which halted the brain oxidative stress, reduced inflammatory cytokines, ameliorated neurotransmitters, and neurochemical release, and suppressed apoptotic genes (p < 0.05). The alleviated antiapoptotic gene expression and histopathological analysis confirmed that the treatment of AuNPs showed significant neural pathways that aid in reducing tissue damage and necrosis. The results emphasize that the biomedical activity was increased by using the green source synthesis P. ligularis -AuNPs. Additionally, the formulation of AuNPs demonstrates strong neuroprotective effects against PPA-induced autism that were arbitrated by a range of different mechanisms, such as anti-inflammatory, antioxidant, neuromodulator, and antiapoptotic effects.

Sensory Metabolite Profiling in a Date Pit Based Coffee Substitute and in Response to Roasting as Analyzed via Mass Spectrometry Based Metabolomics.

Interest in developing coffee substitutes is on the rise, to minimizing its health side effects. In the Middle East, date palm (Phoenix dactylifera L.) pits are often used as a coffee substitute post roasting. In this study, commercially-roasted date pit products, along with unroasted and home-prepared roasted date pits, were subjected to analyses for their metabolite composition, and neuropharmacological evaluation in mice. Headspace SPME-GCMS and GCMS post silylation were employed for characterizing its volatile and non-volatile metabolite profile. For comparison to roasted coffee, coffee product was also included. There is evidence that some commercial date pit products appear to contain undeclared additives. SPME headspace analysis revealed the abundance of furans, pyrans, terpenoids and sulfur compounds in roasted date pits, whereas pyrroles and caffeine were absent. GCMS-post silylation employed for primary metabolite profiling revealed fatty acids' enrichment in roasted pits versus sugars' abundance in coffee. Biological investigations affirmed that date pit showed safer margin than coffee from its LD50, albeit it exhibits no CNS stimulant properties. This study provides the first insight into the roasting impact on the date pit through its metabolome and its neuropharmacological aspects to rationalize its use as a coffee substitute.

Zinc oxide calcium silicate composite attenuates acute tramadol toxicity in mice.

BACKGROUND: Seizures are considered to be the most common symptom encountered in emergency- rushed tramadol-poisoned patients; accounting for 8% of the drug-induced seizure cases. Although, diazepam clears these seizures, the risk of central respiratory depression cannot be overlooked. Henceforth, three adsorbing composites were examined in a tramadol acute intoxication mouse model. METHODS: Calcium Silicate (Wollastonite) either non-doped or wet doped with iron oxide (3%Fe2O3) or zinc oxide (30% ZnO) were prepared. The composites' adsorption capacity for tramadol was determined in vitro. Tramadol intoxication was induced in Swiss albino mice by a parenteral dose of 120 mg/kg. Proposed treatments were administered within 1 min at 5 increasing doses, i.p. The next 30 min, seizures were monitored as an intoxication symptom. Plasma tramadol concentration was recorded after two hours of administration. RESULTS: The 3% Fe2O3-containing composite (CSFe3), was found to be composed of mainly wollastonite with very little alpha-hematite. On the other hand, hardystonite and wellimite were developed in the 30%ZnO-containing composite (CSZn3). Micro-round and irregular nano-sized microstructures were established (The particle size of CS was 56 nm, CSFe3 was 49 nm, and CSZn3 was 42 nm). The CSZn3 adsorption capacity reached 1497 mg of tramadol for each gram. Tramadol concentration was reduced in plasma and seizures were inhibited after its administration to mice at three doses. CONCLUSION: The calcium silicate composite doped with ZnO presented a good resolution of tramadol-induced seizures accompanied by detoxification of blood, indicating its potential for application in such cases. Further studies are required.

Novel, cost-effective, Cu-doped calcium silicate nanoparticles for bone fracture intervention: Inherent bioactivity and in vivo performance.

Copper (Cu)-doped calcium silicate nanoparticles were synthesized by a wet precipitation method as economical bone fracture filler. The aim was to improve the overall physicochemical properties, bioactivity, and biological performance of the bone fracture filler prepared herein. The synthesized nanoparticles were evaluated using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM). The bioactivity of the prepared nanoparticles was investigated after immersion in simulated body fluid (SBF) by means of inductively coupled plasma (ICP), SEM coupled with energy dispersive X-rays (EDX), and FTIR. The size and bioactivity of the prepared nanoparticles after 15 days of immersion in SBF was dependent on the Cu concentrations. The fracture healing ability of the fabricated nanoparticles on adult aged male Wistar rats was enhanced by the presence of copper. All the obtained results are of high relevance for fabricating improved Cu-doped calcium silicate nanoparticles (∼50 nm) as low cost bone fracture filler. In addition, the in vivo study presented complete healing of the tibiae bone with normal architecture of bone tissue specifically calcium silicate nanoparticles doped with 3% and 5% Cu. Hence, the presence of copper is a promising tactic for improving the biological properties of calcium silicate. Therefore, the designed nanoparticles have huge potential for the treatment of bone fractures. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 388-399, 2019.

Determination of delta-9-tetrahydrocannabinol content of cannabis seizures in Egypt.

OBJECTIVE: To determine the delta-9-tetrahydrocannabinol (THC) content of cannabis seizures in Egypt. METHODS: Unheated and heated extracts of cannabis seizures were prepared from the dried flowering tops and leaves (marijuana) or from the resin (hashish) and subjected to analysis using high performance liquid chromatography (HPLC). RESULTS: The heated resin extract had the peak of THC in a relative ratio of 31.34%, while extracting the resin directly without heating contained only 18.34% of THC. On the other hand, marijuana showed minimum percentage of THC at 11.188% on heating and 9.55% without heating. CONCLUSIONS: These results indicate the high potency of the abused cannabis plant in the illicit Egyptian market.

Nanofiber-expanded stem cells mitigate liver fibrosis: Experimental study.

OBJECTIVES: This study examines a pretreatment strategy to strengthen the hepatic lineage divergence of mesenchymal stem cells (MSCs). DESIGN AND METHODS: BMSCs were expanded in the presence or absence of nanofiber (NF) and treated with growth factors (GF) prior to transplantation. Thioacetamide (TA) was used for liver fibrosis induction and transplantation of NF-expanded BMSCs was compared biochemically and histologically to the cells expanded without NF scaffold. RESULTS: The ultraweb NF caused better proliferation and characterization of MSCs. MSCs transplantation significantly improved liver functions, increased hepatic HGF and Bcl-2 levels, whereas decreased serum fibronectin, hepatic TNF-α and TGF-ß1 levels. Hepatic HNF4α, FOXa2, CYP7a1 genes expression were enhanced while ß-5-Tub and AFP genes expression were depressed. Histological study documented these results. Differentiated NF-MSCs showed pronounced enhancement of the aforementioned parameters as compared to differentiated MSCs in the absence of NF. CONCLUSION: pretreatment with growth factors in the presence of NF augment homing, repopulation and hepatic differentiation abilities of MSCs and proves to be a promising approach for the treatment of liver fibrosis.

Neuroprotective effects of bee venom acupuncture therapy against rotenone-induced oxidative stress and apoptosis.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic neurodegeneration, mitochondrial impairment, and oxidative stress. Exposure of animals to rotenone induces a range of responses characteristic of PD, including reactive oxygen species production and dopaminergic cell death. Although l-dopa is the drug of choice for improving core symptoms of PD, it is associated with involuntary movements. The current study was directed to evaluate the neuroprotective effect of bee venom acupuncture therapy (BVA) against rotenone-induced oxidative stress, neuroinflammation, and apoptosis in PD mouse model. Forty male Swiss mice were divided into four groups: (1) received saline solution orally and served as normal control, (2) received rotenone (1.5 mg/kg, s.c. every other day for 6 doses), (3) received rotenone concomitantly with l-dopa (25 mg/kg, daily, p.o. for 6 days), and finally (4) received rotenone concomitantly with BVA (0.02 ml once every 3 days for two weeks). Rotenone-treated mice showed impairment in locomotor behavior and a significant reduction in brain dopamine, serotonin, norepinephrine, GSH levels, and paraoxonase activity, whereas a significant increase was observed in brain malondialdehyde, tumor necrosis factor-α, interleukin-ß levels besides DNA damage, and over-expression of caspase-3, Bax, and Bcl-2 genes. Significant improvement of the aforementioned parameters was demonstrated after BVA compared to l-dopa therapy. In conclusion, bee venom normalized all the neuroinflammatory and apoptotic markers and restored brain neurochemistry after rotenone injury. Therefore, BVA is a promising neuroprotective therapy for PD.