Enviado por Maria el Mié, 08/05/2009.
En el nuevo estudio, el ejercicio con rueda se introdujo mucho antes, cuando los ratones sólo tenían cuatro semanas. Esta vez, el efecto fue mucho mayor. El comienzo de un buen número de déficits motores fue significativamente retardado, aunque la performance en el rotarod acelerado (una medida estándar), no mejoró con el ejercicio voluntario como sucede cuando se enriquece el medio ambiente.
Ya sabemos, basados en el análisis extenso de los datos colectados en un estudio sobre las familias venezolanas con la EH (2004), que el medio ambiente tiene un efecto sobre el comienzo de la enfermedad. El número de repeticiones de CAG se asocia a la edad del comienzo, respecto del nivel de los agregados. En general, aquellos con un mayor número de repeticiones se volverán sintomáticos antes que aquellos con un número bajo. Sin embargo, no es posible predecir la edad del comienzo de la enfermedad para cada individuo porque la edad para dos personas con el mismo número de repeticiones de CAG a menudo varía considerablemente. Una parte de la variación es genética; hay buenas evidencias de que existen genes modificadores.
Sin embargo, otra evidencia apunta a los factores ambientales como otra influencia mayor. La edad del comienzo de la enfermedad puede variar incluso entre gemelos idénticos. El trabajo del dr. Hannan y sus colegas sugiere que los factores ambientales positivos pueden incluir una estimulación cognitiva y sensorial realzada, ejercicio y actividades físicas.
Hasta aquí es hasta donde la investigación respecto del ejercicio y el enriquecimiento del medio ambiente van a llegar. Aunque quizá se realicen nuevos estudios con ratones, no se llevarán a cabo estudios con humanos con un grupo control de perezosos! Pero hay un mensaje claro que los jóvenes en riesgo que hayan dado positivo en el test deben llevarse a casa. No esperen, empiecen con un programa sano de ejercicio ahora mismo. Sigan aprendiendo, desarrollen nuevas habilidades y busquen nuevas experiencias que amplíen sus horizontes intelectuales y culturales.
Referencias:
T.Y.C. Pang, N.C. Stam, J. Nithianantharajah, M.L. Howard, and A.J. Hannan, "Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington's disease transgenic mice." Behavioral Neuroscience 2006; 141(2): 569-584.
Tara L. Spires, Helen E. Grote, Neelash K. Varshney, Patricia M. Cordery, Anton van Dellen, Colin Blakemore, and Anthony J. Hannan, "Environmental Enrichment Rescues Protein Deficits in a Mouse Model of Huntington's Disease, Indicating a Possible Disease Mechanism." The Journal of Neuroscience, 2004 March 3; 24(9): 2270-2276.
The U.S.-Venezuela Collaborative Research Project and Nancy S. Wexler, "Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset." Proc Natl Acad Sci U S A. 2004 March 9; 101(10): 3498-3503.
The simple act of running in an exercise wheel delays the onset of some symptoms of Huntington’s disease in a mouse model of the fatal human disorder according to research published in the open-access journal BMC Neuroscience. These findings add insights into the pathogenesis of the disease and suggest possible preventive therapeutic targets.
Huntington’s disease affects up to one person in every 10 000, but clusters in families and certain populations. Affected people develop clusters of a defective protein in their neurons and shrinkage of brain areas associated with movement. The disorder causes disability and eventually death, but does not normally manifest until after people have had children, allowing the disease gene to be passed on.
“Although Huntington’s disease is considered the epitome of genetic determinism, environmental factors are increasingly recognised to influence the disease progress”, the researchers write.
The research team from the University of Oxford and the Howard Florey Institute, University of Melbourne, report findings of a study in mice with the genetic mutation that causes Huntington’s in humans. Just as mentally stimulating these mice by enriching their environment had previously been shown to delay onset and progression of motor symptoms, so does the simple physical activity of running in a wheel.
“Of particular interest was the fact that the wheel exercise was started in juvenile mice, much earlier than in a previous study that showed more limited protective effects of physical activity”, explains Anthony Hannan of the Howard Florey Institute. This finding suggests that the protective effect has a specific time window.
Hannan notes “Physical activity did not postpone all the motor symptoms delayed by environmental enrichment, which suggests that sensory stimulation, mental exercise, and physical activity could all be used for the benefit of human sufferers”. Early intervention is also possible in people who will develop Huntington’s, because genetic diagnosis is possible.
Density of protein aggregates in neurons and shrinkage in brain regions in mice that had benefited from physical activity were as advanced as in those raised without wheels, the authors suggest therefore that benefits stem from stimulation of neuronal receptors and other molecules that prolongs normal function and delays motor deficits.
The Journal Abstract
Background
Huntington's disease (HD) is a neurodegenerative disorder predominantly affecting the cerebral cortex and striatum. Transgenic mice (R6/1 line), expressing a CAG repeat encoding an expanded polyglutamine tract in the N-terminus of the huntingtin protein, closely model HD. We have previously shown that environmental enrichment of these HD mice delays the onset of motor deficits. Furthermore, wheel running initiated in adulthood ameliorates the rear-paw clasping motor sign, but not an accelerating rotarod deficit.
Results
We have now examined the effects of enhanced physical activity via wheel running, commenced at a juvenile age (4 weeks), with respect to the onset of various behavioral deficits and their neuropathological correlates in R6/1 HD mice. HD mice housed post-weaning with running wheels only, to enhance voluntary physical exercise, have delayed onset of a motor co-ordination deficit on the static horizontal rod, as well as rear-paw clasping, although the accelerating rotarod deficit remains unaffected. Both wheel running and environmental enrichment rescued HD-induced abnormal habituation of locomotor activity and exploratory behavior in the open field. We have found that neither environment enrichment nor wheel running ameliorates the shrinkage of the striatum and anterior cingulate cortex (ACC) in HD mice, nor the overall decrease in brain weight, measured at 9 months of age. At this age, the density of ubiquitinated protein aggregates in the striatum and ACC is also not significantly ameliorated by environmental enrichment or wheel running.
Conclusions
These results indicate that enhanced voluntary physical activity, commenced at an early presymptomatic stage, contributes to the positive effects of environmental enrichment. However, sensory and cognitive stimulation, as well as motor stimulation not associated with running, may constitute major components of the therapeutic benefits associated with enrichment. Comparison of different environmental manipulations, performed in specific time windows, can identify critical periods for the induction of neuroprotective 'brain reserve' in animal models of HD and related neurodegenerative diseases.