A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats

Paclitaxel is an effective antineoplastic drug treatment used as an anti-tumoral therapy. Unfortunately its use is associated with unwanted side effects, which include the development of peripheral neuropathies and neuropathic pain, greatly affecting the quality of life of patients. It is well known that agonists of the cannabinoid receptor are able to reduce hyperalgesia and allodynia that develop after nerve injury. Our aim was to evaluate the efficacy of the cannabinoid agonist WIN 55,212-2 to reduce the thermal hyperalgesia and the tactile allodynia induced by administration of paclitaxel in rats. Present results demonstrate that WIN 55,212-2 (1 mg/kg i.p.) significantly reduced the heat (P<0.0001) and the mechanical (P=0.0003) withdrawal thresholds, the dose being smaller than that required to reach similar effects in the sciatic nerve constriction model (1.5 mg/kg). When the cannabinoid tetrad test was evaluated to measure behavioral modifications, it was found that WIN 55,212-2 (1mg/kg) did not induce changes either in body temperature or in immobility time, and only a reduction in spontaneous motility was recorded. This effect was antagonized by SR 141716A, suggesting the involvement of the CB1 receptor, although the participation of CB2 receptors cannot be excluded from this study. When WIN 55,212-2 was administered intraplantar, no differences were observed between the injected paw and the contralateral paw, suggesting that systemic mechanisms are needed to reach effectiveness. From these results we suggest that cannabinoids may be an interesting alternative to reduce neuropathic symptoms induced by paclitaxel, however more work is required to assess this possibility.     

Adipose stromal vascular fraction improves cardiac function in chronic myocardial infarction through differentiation and paracrine activity

Fresh adipose-derived cells have been shown to be effective in the treatment of acute myocardial infarction (MI), but their role in the chronic setting is unknown. We sought to determine the long-term effect of the adipose derived-stromal vascular fraction (SVF) cell transplantation in a rat model of chronic MI. MI was induced in 82 rats by permanent coronary artery ligation and 5 weeks later rats were allocated to receive an intramyocardial injection of 10(7) GFP-expressing fresh SVF cells or culture media as control. Heart function and tissue metabolism were determined by echocardiography and (18)F-FDG-microPET, respectively, and histological studies were performed for up to 3 months after transplantation. SVF induced a statistically significant long-lasting (3 months) improvement in cardiac function and tissue metabolism that was associated with increased revascularization and positive heart remodeling, with a significantly smaller infarct size, thicker infarct wall, lower scar fibrosis, and lower cardiac hypertrophy. Importantly, injected cells engrafted and were detected in the treated hearts for at least 3 months, directly contributing to the vasculature and myofibroblasts and at negligible levels to cardiomyocytes. Furthermore, SVF release of angiogenic (VEGF and HGF) and proinflammatory (MCP-1) cytokines, as well as TIMP1 and TIMP4, was demonstrated in vitro and in vivo, strongly suggesting that they have a trophic effect. These results show the potential of SVF to contribute to the regeneration of ischemic tissue and to provide a long-term functional benefit in a rat model of chronic MI, by both direct and indirect mechanisms.     

Evaluation and Management of Outlet Obstruction in Women Without Anatomical Abnormalities on Physical Exam or Cystoscopy

Bladder outlet obstruction (BOO) in women can be either anatomic or functional. Anatomic causes for BOO are often readily apparent by history and physical exam. On the other hand, causes for functional obstruction, including dysfunctional voiding, primary bladder neck obstruction, and detrusor-external sphincter dyssynergia, are more difficult to establish. Because the appropriate treatment for functional obstruction drastically varies according to etiology, making an accurate diagnosis is paramount. Videourodynamics, interpreted in the context of individual clinical symptoms, remains the diagnostic gold standard in women with functional obstruction.     

Metabolic changes by acute insulin deficiency in rabbits injected with anti-insulin serum

Summary Acute insulin deficiency was produced in rabbits treated with anti-insulin guinea pig serum. The changes in the levels of blood sugar, free fatty acids, aceto-acetate, SGOT, SGPT, liver glutamicoxaloacetic and glutamic-pyruvic transaminases, and liver lactate dehydrogenase were examined. A significant increase of the blood glucose level and the free fatty acids as well as glycosuria was observed. The other examined parameters remained unchanged. The results confirm the statement that acute insulin deficiency causes a prompt impairment of glucose and fat metabolism.

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Zusammenfassung Ein akuter Insulin-Mangelzustand wurde in mit anti-Insulinserum vom Meerschweinchen behandelten Kaninchen hervorgerufen. Es wurden die Veraenderungen des Blutzuckerspiegels, der freien Fettsaeuren, des Azetoazetats, der SGOT, SGPT, der Glutaminsaeure-Oxalessigsaeure-Transaminase und der Glutaminsaeure-Pyruvat-Transaminase, sowie der LDH in der Leber untersucht. Es wurde eine signifikante Steigerung des Blutzuckers, der freien Fettsaeuren und auch des Harnzuckers festgestellt. Die anderen untersuchten Parameter blieben unveraendert. Die Resultate bestaetigen den Tatbestand, dass der akute Insulinmangelzustand eine sofortige Stoerung des Kohlenhydrat- sowie des Fettstoffwechsels ausloest.

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Resumen Una carencia insulínica aguda ha sido provocada en los conejos tratados con suero de cobayo anti-insulina. Han sido estudiadas las variaciones en los niveles de la glucemia, de los ácidos grasos libres, del acetoacetato, de la SGOT, de la SGPT, de las transaminasas glutámico-oxaloacética y glutámico-pirúvica hepáticas y de la láctico-dehidrogenasa hepática. Ha sido puesto de manifiesto un aumento significativo de la glucemia y de los ácidos grasos libres, y también de la glucosuria. Los otros parámetros examinados han quedado invariados. Los resultados ratifican el hecho de que la carencia aguda de insulina provoca una alteración inmediata en el metabolismo de los glúcidos y de los lípidos.

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Resume On a provoqué une carence en insuline aïgue chez des lapins traités au sérum de cobaye antiinsuline. On a étudié les variations de taux de glycémie, des acides gras libres, d'acéto-acétate, de SGOT, de SGPT, des transaminases glutamique oxalacétique et glutamico-pyruvique hépatiques ainsi que de la déshydrogénase lactique hépatique. On a observé une augmentation significative de la glycémie et des acides gras libres, et même de la glycosurie. Les autres paramètres étudiés sont restés inchangés. Les résultats confirment le fait que la carence aïgue en insuline provoque une perturbation immédiate du métabolisme des glucides et des lipides.

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Riassunto Una carenza insulinica acuta è stata provocata nei conigli trattati con siero di cavia anti-insulina. Sono state studiate le variazioni del livello della glicemia, degli acidi grassi liberi, dell'acetoacetato, della SGOT, della SGPT, delle transaminasi glutammico-ossalacetica e glutammico-piruvica epatiche e della lattico deidrogenasi epatica. E' stato rilevato un aumento significativo della glicemia e degli acidi grassi liberi, ed anche della glicosuria. Gli altri parametri esaminati sono rimasti invariati. I risultati confermano il fatto che la carenza acuta di insulina provoca un disturbo immediato del metabolismo glucidico e lipidico.

     

Prostaglandin E2-increased thermosensitivity of anterior hypothalamic neurons is associated with depressed inhibition

Temperature responses of anterior hypothalamic neurons are considered key elements in the regulation of the temperature setpoint of homeotherms. We have investigated the sensitivity to warming of cultured neurons of the AH from mice with electrophysiological and immunocytochemical techniques. In control experiments, only approximately 9% of the 3- to 5-week-old cells exhibited changes of their basic firing rate when the temperature was raised from 37 degrees C to 40 degrees C. This ratio was increased to 27% after the cultures were "primed" by adding prostaglandin E2 (PGE2), an endogenous pyrogen, in the extracellular medium. In these neurons the firing rate was significantly increased, and the frequency of the gamma gamma-aminobutyric acid (GABA) inhibitory postsynaptic potentials was markedly decreased. In contrast, the resting potential and membrane resistance of the recorded cells remained unchanged. PGE2 was found to decrease the level of phosphorylation of the extracellular signal-regulated kinases 1 and 2 in a subset of GABAergic neurons that express the E-prostanoid receptor type 3. Inhibition of ERK1/2 by U0126 mimicked the effects of PGE2. These data indicate that PGE2 acts primarily on the excitability of GABAergic presynaptic cells, most likely via alterations of voltage-gated K+ channels. Our results also suggest that far from being an inherent property of a specialized class of neurons, the degree of thermosensitivity can be strongly modulated by synaptic activity and is a more adaptive property of hypothalamic neurons than previously thought.