Evidence is now overwhelming that inflammation is a central process in the pathogenesis of progressive Parkinson's disease PD . The hallmark of this neuroinflammation is the activation of microglial cells and the secondary role of adaptive immunity in both the familial and idiopathic forms of PD, leading to the loss of dopamine-producing cells within the Substantia nigra. This activation is characterized by the oxidative stress response, production of inflammatory mediators, recruitment and activation of immune effector cells which create a toxic environment for dopaminergic neurons, and in forming a continuous cycle of inflammatory responses that result in chronic neuroinflammation and progressive neurodegeneration. This chapter focuses on the different components of the inflammatory response that are involved in Dopamine-neurodegeneration, the evidence for inflammation in different forms of PD, and the role of inflammation in the various animal models of PD. Finally, we provide current evidence that targeting this inflammation with a number of anti-inflammatory therapies can be an effective way to halt the progression of chronic neuroinflammation-induced PD.
When quadrupeds stop walking after stepping over a barrier with their forelegs, the memory of barrier height and location is retained for many minutes. This memory is subsequently used to guide hind leg movements over the barrier when walking is resumed. The upslope of the initial trajectory of hind leg paw movements is strongly dependent on the initial location of the paw relative to the barrier. In this study, we have attempted to determine whether mechanical factors contribute significantly in establishing the slope of the paw trajectories by creating a four-link biomechanical model of a cat hind leg and driving this model with a variety of joint-torque profiles, including average torques for a range of initial paw positions relative to the barrier. Torque profiles for individual steps were determined by an inverse dynamic analysis of leg movements in three normal cats. Our study demonstrates that limb mechanics can contribute to establishing the dependency of trajectory slope on the initial position of the paw relative to the barrier. However, an additional contribution of neuronal motor commands was indicated by the fact that the simulated slopes of paw trajectories were significantly less than the observed slopes. A neuronal contribution to the modification of paw trajectories was also revealed by our observations that both the magnitudes of knee flexor muscle EMG bursts and the initial knee flexion torques depended on initial paw position. Previous studies have shown that a shift in paw position prior to stepping over a barrier changes the paw trajectory to be appropriate for the new paw position. Our data indicate that both mechanical and neuronal factors contribute to this updating process, and that any shift in leg position during the delay period modifies the working memory of barrier location.
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