Showing papers by "Vicente Felipo published in 2011"

p38 MAP kinase is a therapeutic target for hepatic encephalopathy in rats with portacaval shunts

Abstract: Objective Inflammation plays a role in neurological alterations in patients with hepatic encephalopathy (HE). Animal models of HE show neuroinflammation. Treatment with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), reduces neuroinflammation and restores cognitive and motor function in rats with HE due to portacaval shunts (PCS). This suggests that reducing neuroinflammation would improve neurological status in patients with minimal or clinical HE. NSAID induce kidney damage in patients with cirrhosis and PCS rats and are not suitable for clinical use. It is therefore necessary to look for procedures to eliminate neuroinflammation without inducing secondary effects in the kidney. Inhibition of p38 MAPK is being tested as a therapeutic target in inflammatory diseases and reduces microglial activation. This study aimed to assess whether inhibiting p38 with SB239063 reduces neuroinflammation and improves cognitive and motor function in PCS rats without affecting the kidney. Results p38 activity is increased in the brains of PCS rats and treatment with SB239063 reduces microglial activation, as well as inflammatory markers in brain (prostaglandin E2, cyclooxygenase activity, iNOS, IL-1β, TNFα) and blood (prostaglandin E2 and TNFα). PCS rats showed increased ammonia and glutamine in the brain, which was not affected by SB239063. PCS rats showed reduced ability to learn a Y-maze conditional discrimination task, reduced motor activity and impaired motor coordination, as assessed in the rotarod. Treatment with SB239063 completely restored learning ability, motor activity and coordination in PCS rats. SB239063 did not affect creatinine or sodium levels in serum, indicating that it does not induce kidney damage. Conclusion These findings suggest that reducing neuroinflammation by using inhibitors of p38 would improve the neurological status in HE without inducing secondary effects in the kidney.

BASIC—LIVER, PANCREAS, AND BILIARY TRACT Brain Region-Selective Mechanisms Contribute to the Progression of Cerebral Alterations in Acute Liver Failure in Rats

Abstract: BACKGROUND & AIMS: Patients with acute liver failure (ALF) often die of intracranial pressure (IP) and cerebral herniation. Main contributors to increased IP are ammonia, glutamine, edema, and blood flow. The sequence of events and underlying mechanisms, as well as the temporal pattern, regional distribution, and contribution of each parameter to the progression of neurologic deterioration and IP, are unclear. We studied rats with ALF to follow the progression of changes in ammonia, glutamine, grade and type (vasogenic or cytotoxic) of edema, blood-brain barrier permeability, cerebral blood flow, and IP. We assessed whether the changes in these parameters were similar between frontal cortex and cerebellum and evaluated the presence, type, and progression of edema in 12 brain areas. METHODS: ALF was induced by injection of galactosamine. The grade and type of edema was assessed by measuring the apparent diffusion coefficient by magnetic resonance imaging. Cerebral blood flow was measured by magnetic resonance and blood-brain barrier permeability by Evans blue‐albumin extravasation. RESULTS: Increased IP arises from an early increase of blood‐brain barrier permeability in certain areas (including cerebellum but not frontal cortex) followed by vasogenic edema. Ammonia and glutamine then increase progressively, leading to cytotoxic edema in many areas. Alterations in lactate and cerebral blood flow are later events that further increase IP. CONCLUSIONS: Different mechanisms in specific regions of the brain contribute, with different temporal patterns, to the progression of cerebral alterations and IP in ALF.

Ultrasound bioeffects in rats: quantification of cellular damage in the fetal liver after pulsed Doppler imaging

Abstract: Objective To determine whether pulsed Doppler examination of the ductus venosus in rat fetuses could damage exposed tissue. Methods On gestational day 18, the livers of a mean of approximately five fetuses per mother (n = 5.14, SD = 1.6), in a cohort of 35 pregnant female rats, were exposed individually to pulsed Doppler and these were considered the ‘exposed group’. The remaining fetuses in each pregnant rat (n = 5.16, SD = 2.1) formed the ‘control group’. We tested for 600, 300, 60, 20, 15, 10 and 3 s of exposure of the fetal ductus venosus and the damage was evaluated measuring a cell death index of apoptotic activity at 7 h post-exposure (n = 16). In addition, subgroups of mothers were sacrificed at 2, 4, 5, 7, 12 and 24 h post-exposure to determine when the damage appeared and disappeared and whether this depended on the exposure time. Results After exposure of 20 s or more, we observed significant damage, as assessed by caspase 3 activity (a marker of apoptotic activity related to tissue damage), in all cases; after 15 s of exposure, some samples presented damage (P = 0.4); there was no damage after 10 s or 3 s of exposure (P = 0.87 and P = 0.3, respectively). There was a positive linear correlation between apoptotic index and pulsed Doppler exposure time, (Pearson's coefficient = 0.324, P 0.05 and P > 0.4). Conclusions We observed reversible damage after pulsed Doppler imaging in an in-vivo fetal liver tissue rat model and found that longer exposure times produced more tissue damage. We established that 10 s was the maximum exposure time to ensure absence of damage to tissue in this model. It would appear sensible to recommend expert supervision of pulsed Doppler imaging and to have intervals between subsequent examinations. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

cGMP modulates stem cells differentiation to neurons in brain in vivo pathological implications

Abstract: During brain development there is a strict control of the proliferation, migration and differentiation of neural stem cells to different cell types. Alterations in the control of these processes may result in altered balance in the formation of different cell types resulting in a long-lasting impairment of cerebral processes. This occurs for example if brain is exposed to alcohol during key stages of development which results in accelerated glial cells formation, impaired neuron formation and impaired cognitive function. The molecular mechanisms modulating differentiation of neural stem cells to neurons or non neuronal cells are not well known. Nitric oxide (NO) plays a relevant role in this process. NO increases the activity of soluble guanylate cyclase and is a main modulator of cGMP levels in brain. It has been proposed that cGMP-mediated NO signalling may be involved in the early differentiation events of embryonic stem cells. If this is the case, pathological situations in which the production of cGMP is altered during brain development could lead to altered differentiation of stem cells to neurons or glial cells, resulting in cognitive impairment in the children. Moreover, normalizing cGMP levels in these situations could prevent the alterations in neural stem cells differentiation and cognitive impairment.