RESUMEN

Doxorubicin is an anthracycline antibiotic that is used for the treatment of various types of cancer. However, its clinical usage is limited due to its potential life-threatening adverse effects, such as cardio- and nephrotoxicities. Nonetheless, simultaneous administration of doxorubicin and antioxidants, such as those found in green tea leaves, could reduce cardiac and renal tissue damage caused by oxidative stress. The methylxanthine fraction isolated from Bancha tea leaves were tested in vitro for its antioxidant activity and in vivo for its organoprotective properties against doxorubicin-induced cardio- and nephrotoxicities in a rat model. The in vivo study was conducted on male Wistar rats divided into 6 groups. Methylxanthines were administered at high (5 mg/kg body weight) and low (1 mg/kg body weight) doses, while doxorubicin was administered at a cumulative dose of 20 mg/kg body weight. Serum creatinine, uric acid, and urea concentrations, as well as serum enzyme levels (creatinine kinase (CK), creatinine kinase MB fraction (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)) and electrolytes (Na+, K+, and Cl-), were analysed. In addition, histological analysis was performed to assess cardiac and renal tissue damage. The concomitant administration of Bancha methylxanthines and doxorubicin showed a dose-dependent reduction in the serum biochemical parameters, indicating a decrease in the cardiac and renal tissue damage caused by the antibiotic. Histological analysis showed that pretreatment with methylxanthines at the dose of 5 mg/kg resulted in an almost normal myocardial structure and a significant decrease in the morphological kidney changes caused by doxorubicin exposure compared with the group that received doxorubicin alone. The putative mechanism is most likely related to a reduction in the oxidative stress caused by doxorubicin.

Asunto(s)

RESUMEN

Background The treatment of heart failure patients is very complex and includes lifestyle modification as well as different pharmacological therapies. Polypharmacy is very common in such patients and they are at increased risk of potential drug-drug interactions and associated effects such as poor adherence, compliance and adverse events. Objective The aim of the present study is to investigate retrospectively the prescribed pharmacotherapy of the hospital discharged heart failure patients for possible drug interactions. Settings Clinic for Cardiology of the "Saint Marina" University Hospital in Varna, Bulgaria. Method Lexicomp® Drug interaction software was used for screening potential drug-drug interactions. Logistic regression was applied to determine the odds ratio for the association between the age and number of drugs taken and the number of potential drug-drug interactions. Main outcome measure Incidence and type of pDDIs in geriatric heart failure patients. Results A retrospective study was conducted by reviewing the medical records of 248 selected heart failure patients for the prescribed medicines for a 1-year period (January 2015-December 2015). The total number of potential drug-drug interactions was 1532, or approximately 6.28 (± 4.72 SD) per one person. The range of prescribed drugs was between three and fourteen, 92% of them have been taking more than five medicines, an average of 7.12 (± 2.07 SD) per patient. The average age was 72.35 (± 10.16 SD). The results have shown stronger association between the number of drugs taken (more than 7) and the occurrence of potential drug-drug interactions (more than 10)-37.84 (95% CI 9.012-158.896, P ≤ 0.001). No statistically significant differences were found between age and occurrence of potential drug-drug interactions (more than 10)-1.008 (95% CI 0.441-2.308, P = 0.848). Conclusion The incidence of drug-drug interactions in heart failure patients is high. The clinical pharmacist, as a part of the multidisciplinary team, could reduce medication-related problems, such as drug interactions, and to optimize drug therapy by checking the treatment prescribed at the discharge of these patients.

Asunto(s)

RESUMEN

Neurodegenerative diseases are disabling, incurable, and progressive conditions characterized by neuronal loss and decreased cognitive function. Changes in gut microbiome composition have been linked to a number of neurodegenerative diseases, indicating a role for the gut-brain axis. Here, we show how specific gut-derived bacterial strains can modulate neuroinflammatory and neurodegenerative processes in vitro through the production of specific metabolites and discuss the potential therapeutic implications for neurodegenerative disorders. A panel of fifty gut bacterial strains was screened for their ability to reduce pro-inflammatory IL-6 secretion in U373 glioblastoma astrocytoma cells. Parabacteroides distasonis MRx0005 and Megasphaera massiliensis MRx0029 had the strongest capacity to reduce IL-6 secretion in vitro. Oxidative stress plays a crucial role in neuroinflammation and neurodegeneration, and both bacterial strains displayed intrinsic antioxidant capacity. While MRx0005 showed a general antioxidant activity on different brain cell lines, MRx0029 only protected differentiated SH-SY5Y neuroblastoma cells from chemically induced oxidative stress. MRx0029 also induced a mature phenotype in undifferentiated neuroblastoma cells through upregulation of microtubule-associated protein 2. Interestingly, short-chain fatty acid analysis revealed that MRx0005 mainly produced C1-C3 fatty acids, while MRx0029 produced C4-C6 fatty acids, specifically butyric, valeric and hexanoic acid. None of the short-chain fatty acids tested protected neuroblastoma cells from chemically induced oxidative stress. However, butyrate was able to reduce neuroinflammation in vitro, and the combination of butyrate and valerate induced neuronal maturation, albeit not to the same degree as the complex cell-free supernatant of MRx0029. This observation was confirmed by solvent extraction of cell-free supernatants, where only MRx0029 methanolic fractions containing butyrate and valerate showed an anti-inflammatory activity in U373 cells and retained the ability to differentiate neuroblastoma cells. In summary, our results suggest that the pleiotropic nature of live biotherapeutics, as opposed to isolated metabolites, could be a promising novel drug class in drug discovery for neurodegenerative disorders.

RESUMEN

About half of patients with spinal cord injury (SCI) develop debilitating central neuropathic pain (CNP), with no effective treatments. Thus, effective, safe, and novel therapies are needed urgently. Previously, docosahexaenoic acid (DHA) was reported to confer neuroprotection in preclinical SCI models. However, its therapeutic potential on SCI-CNP remains to be elucidated. Here, we demonstrated for the first time that intravenous DHA administrations with 3-day intervals (250 nmol/kg; starting 30 minutes after injury and maintained for 6 weeks) effectively prevented SCI-CNP development in a clinically relevant rat contusion model. SCI-CNP was assessed by a novel sensory profiling approach combining evoked pain measures and pain-related ethologically relevant rodent behaviours (burrowing, thigmotaxis, and place/escape avoidance) to mimic those for measuring human (sensory, affective, cognitive, and spontaneous) pain. Strikingly, already established SCI-CNP could be abolished partially by similar DHA administrations, starting from the beginning of week 4 after injury and maintained for 4 weeks. At spinal (epicenter and L5 dorsal horns) and supraspinal (anterior cingulate cortex) levels, both treatment regimens potently suppressed microglial and astrocyte activation, which underpins SCI-CNP pathogenesis. Spinal microgliosis, a known hallmark associated with neuropathic pain behaviours, was reduced by DHA treatments. Finally, we revealed novel potential roles of peroxisome proliferator-activated and retinoid X receptors and docosahexaenoyl ethanolamide (DHA's metabolite) in mediating DHA's effects on microglial activation. Our findings, coupled with the excellent long-term clinical safety of DHA even in surgical and critically ill patients, suggest that systemic DHA treatment is a translatable, effective, safe, and novel approach for preventing and managing SCI-CNP.

Asunto(s)

RESUMEN

BACKGROUND: Primary microglial cultures have been used extensively to facilitate the development of therapeutic strategies for a variety of CNS disorders including neurodegeneration and neuropathic pain. However, existing techniques for culturing these cells are slow and costly. NEW METHOD: Here, we report a refined protocol based on our previously published methods described by Clark et al., which reduces in the time, reagents and the number of animals used for each culture whilst yielding high number and excellent quality microglial cells. RESULTS: Our refined protocol offers an isolation of >96% microglia from a mixed glial culture after only four days of incubation. It results in a high yield of microglia, in excess of one million cells per cortex with predominantly resting morphology and a low level of cell activation. COMPARISON WITH EXISTING METHOD(S): Compared to conventional procedures our refined protocol requires only one third of the time to prepare high quality microglial cultures, cuts the cost more than four-fold, and significantly reduces the number of animals used per culture. CONCLUSION: Our consistent, reliable, and time/cost effective microglial culture protocol is crucial for efficient in vitro screening of potential therapeutics. By dramatically reducing the culture time from 2 weeks to just 4 days and increasing the laboratory research output it has implications for the Reduction, Refinement and Replacement policies endorsed by many government funding agencies and animal research regulatory bodies.

Asunto(s)