Metformin inhibits paclitaxel-induced mechanical allodynia by activating opioidergic pathways and reducing cytokines production in the dorsal root ganglia and thalamus.

It has been shown that AMP-activated protein kinase (AMPK) is involved in the nociceptive processing. This observation has prompted us to investigate the effects of the AMPK activator metformin on the paclitaxel-induced mechanical allodynia, a well-established model of neuropathic pain. Mechanical allodynia was induced by four intraperitoneal (i.p) injections of paclitaxel (2 mg/kg.day) in mice. Metformin was administered per os (p.o.). Naltrexoneandglibenclamide were used to investigate mechanisms mediating metformin activity. Concentrations of cytokines in the dorsal root ganglia (DRG) and thalamus were determined. After a single p.o. administration, the two highest doses of metformin (500 and 1000 mg/kg) attenuated the mechanical allodynia. This response was attenuated by all doses of metformin (250, 500 and 1000 mg/kg) when two administrations, 2 h apart, were carried out. Naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, p.o.), attenuated metformin activity. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and CXCL-1 in the DRG were increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentrations of TNF-α, IL-1ß and CXCL-1 in the DRG. Concentration of IL-6, but not TNF-α, in the thalamus was increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentration of IL-6 in the thalamus. In summary, metformin exhibits activity in the model of neuropathic pain induced by paclitaxel. This activity may be mediated by activation of opioidergic pathways and reduced production of TNF-α, IL-1ß and CXCL-1 in the DRG and IL-6 in the thalamus.

Synthesis of 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione, a novel hydrogen sulfide-releasing phthalimide hybrid, and evaluation of its activity in models of inflammatory pain.

Hydrogen sulfide (H2S) is a gaseous mediator that modulates several physiological and pathological processes. Phthalimide analogues, substances that have the phthalimide ring in the structure, belong to the group of thalidomide analogues. Both H2S donors and phthalimide analogues exhibit activities in models of inflammation and pain. As molecular hybridization is an important strategy aiming to develop drugs with a better pharmacological profile, in the present study we synthesized a novel H2S-releasing phthalimide hybrid, 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione (PTD-H2S), and evaluated its activity in models of inflammatory pain in mice. Per os (p.o.) administration of PTD-H2S (125 or 250 mg/kg) reduced mechanical allodynia induced by carrageenan and lipopolysaccharide. Intraperitoneal (i.p.) administration of PTD-H2S (25 mg/kg), but not equimolar doses of its precursors 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (14.2 mg/kg) and 2-phthalimidethanol (12 mg/kg), reduced mechanical allodynia induced by lipopolysaccharide. The antiallodynic effect induced by PTD-H2S (25 mg/kg, i.p.) was more sustained than that induced by the H2S donor NaHS (8 mg/kg, i.p.). Previous administration of hydroxocobalamin (300 mg/kg, i.p.) or glibenclamide (40 mg/kg, p.o.) attenuated PTD-H2S antiallodynic activity. In conclusion, we synthesized a novel H2S-releasing phthalimide hybrid and demonstrated its activity in models of inflammatory pain. PTD-H2S activity may be due to H2S release and activation of ATP-sensitive potassium channels. The demonstration of PTD-H2S activity in models of pain stimulates further studies aiming to evaluate H2S-releasing phthalimide hybrids as candidates for analgesic drugs.

RI75, a curcumin analogue, inhibits tumor necrosis factor-α and interleukin-6 production and exhibits antiallodynic and antiedematogenic activities in mice.

Curcumin and its analogues exhibited anti-inflammatory activity in different experimental models. Recently, we synthesized (2E,3E)-3-buten-2-one-4-(4-hydroxy-3-methoxyphenyl)-2-(4-(4-methoxyphenyl)-2-thiazolyl)hydrazone (RI75), a curcumin analogue with a thiazolyl hydrazone moiety. In the present study, we investigated the effects induced by RI75 in different models of inflammation and pain in mice, as well as some underlying mechanisms. Pre-treatment with RI75 (40 mg/kg, intraperitoneal; i.p.) or curcumin (40 mg/kg, i.p.) reduced the mechanical allodynia and paw edema induced by intraplantar (i.pl) injection of carrageenan. RI75 antiallodynic activity was reduced by pre-treatment with naltrexone (5 and 10 mg/kg, i.p.) and cyproheptadine (10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, i.p.). In a model of neuropathic pain, a single i.p. administration of RI75 (40 mg/kg) or curcumin (40 mg/kg) attenuated the ongoing mechanical allodynia induced by repeated administrations of paclitaxel. Pre-treatment with RI75 (40 mg/kg, i.p.) or curcumin (40 mg/kg, i.p.) also reduced tumor necrosis factor-α and interleukin-6 production and myeloperoxidase activity induced by carrageenan. The results of the present study demonstrate that RI75, a synthetic curcumin analogue, exhibits antiallodynic and antiedematogenic activities. Activation of opioidergic and serotonergic mechanisms and reduced production of inflammatory mediators and neutrophil recruitment may underlie RI75 activities.

[Diagnosis of brain death by multislice CT scan: angioCT scan and brain perfusion]. / Diagnóstico de muerte encefálica mediante tomografía computarizada multicorte: angio-TC y perfusión cerebral.

BD was diagnosed by clinical examination, electroencephalogram (EEG), Transcranial Doppler (TCD) and multislice CT of 64 detectors. Initially, a brain perfusion study was performed. This was followed by supra-aortic trunk and brain artery angiography with acquisition of images using 0.5 mm slices, from the origin of the aortic root to the vertex. In all the patients, BD diagnosis was verified by clinical examination, EEG and TCD. Brain perfusion never detected brain blood flow. The angioCT through internal carotid arteries and vertebral arteries demonstrated complete absence of intracranial circulation, observing circulation of the external carotid artery branches. Sensitivity and specificity of the method compared with clinical examination was 100%. These findings demonstrate that the study of brain perfusion and brain angiography by multislice CT scan is a rapid and minimally invasive technique, that is easily available and that shows the absence of brain blood flow through the four vascular trunks. This technique makes it possible to made the diagnosis of BD with high diagnostic safety. Its use has special interest in patients with clinical diagnostic difficulty due to treatment with sedative drugs and serious metabolic alterations.

Diagnóstico de muerte encefálica mediante tomografía computarizada multicorte: angio-TC y perfusión cerebral / Diagnosis of brain death by multislice CT scan: angioCT scan and brain perfusion

El objetivo del presente estudio fue valorar la perfusión cerebral y la angiografía cerebral mediante tomografía computarizada (TC) multicorte, como método diagnóstico de muerte encefálica (ME). Fueron analizados 6 pacientes ingresados en una Unidad de Cuidados Intensivos, con patología neurológica grave y posterior evolución a ME. El diagnóstico de ME se realizó mediante exploración clínica, electroencefalograma (EEG), doppler transcraneal (DTC) y TC multicorte de 64 detectores. Inicialmente se realizó un estudio de perfusión cerebral, seguido de angiografía de troncos supraaórticos y arterias cerebrales con adquisición de imágenes mediante cortes de 0,5 mm, desde el nacimiento de la raíz de aorta hasta el vértex. En todos los pacientes se confirmó el diagnóstico de ME mediante exploración clínica, EEG y DTC. En ningún caso la perfusión cerebral detectaba flujo sanguíneo cerebral. La angio-TC a través de arterias carótidas internas y arterias vertebrales demostraba una ausencia completa de circulación intracraneal visualizándose circulación en ramas de las arterias carótidas externas. La sensibilidad y especificidad del método comparada con la exploración clínica fue del 100%. Estos hallazgos demuestran que el estudio de perfusión cerebral y la angiografía cerebral mediante TC multicorte es una técnica rápida, mínimamente invasiva, de fácil disponibilidad y que demuestra la ausencia de flujo sanguíneo cerebral a través de los 4 troncos vasculares. Esta técnica permite realizar el diagnóstico de ME con una gran seguridad diagnóstica. Su uso tiene especial interés en pacientes con dificultad diagnóstica clínica por tratamiento con fármacos sedantes y graves alteraciones metabólicas

BD was diagnosed by clinical examination, electroencephalogram (EEG), Transcranial Doppler (TCD) and multislice CT of 64 detectors. Initially, a brain perfusion study was performed. This was followed by supra-aortic trunk and brain artery angiography with acquisition of images using 0.5 mm slices, from the origin of the aortic root to the vertex. In all the patients, BD diagnosis was verified by clinical examination, EEG and TCD. Brain perfusion never detected brain blood flow. The angioCT through internal carotid arteries and vertebral arteries demonstrated complete absence of intracranial circulation, observing circulation of the external carotid artery branches. Sensitivity and specificity of the method compared with clinical examination was 100%. These findings demonstrate that the study of brain perfusion and brain angiography by multislice CT scan is a rapid and minimally invasive technique, that is easily available and that shows the absence of brain blood flow through the four vascular trunks. This technique makes it possible to made the diagnosis of BD with high diagnostic safety. Its use has special interest in patients with clinical diagnostic difficulty due to treatment with sedative drugs and serious metabolic alterations

[Stereotactic target identification for neurosurgery of Parkinson disease]. / Identificación de las dianas estereotáxicas en la cirugía de la enfermedad de Parkinson.

INTRODUCTION: The use of applied neurophysiological methods to improve the stereotactic localization of devices in the deep human brain is a high and systematic technology in Parkinson's neurosurgery today. The available standard equipment for clinical neurophysiology practice may constitute the basic set for high tech functional neurosurgery. Free run and event related multiunit recording, naturalistic and electrical evoked potentials, and deep brain microstimulation responses are the basic methodological set to neurophysiological target localization. DEVELOPMENT AND CONCLUSIONS: This article is concerned with the topic: set out a high technology using low cost equipment. So our 41 cases experienced in pallidal and thalamic nucleolisis and thalamus and subthalamus DBS results suggest that the proposed equipment and methods are the required to assure accuracy and safety for target location.

Actinomycotic brain abscess: CT findings.

An unusual case of actinomycotic brain abscess with histologic documentation is reported. Commonly, a primary focus of actinomycosis in the cervicofacial, thoracic, or abdominal areas is found. In our particular case such a primary source of infection was not evident. Cranial CT showed a thick-walled ring enhancing lesion deeply located in the left parietal region. This CT finding was useful but not diagnostically pathognomonic. Correct diagnosis was made based on histologic findings. Sulfur granules and Gram-positive branching organisms were seen in the purulent material.