Page 6 of 13 http://www.translationalneurodegeneration.com/content/1/1/9 model of experimental allergic encephalomyelitis (EAE) [157] , the inhibition of microglial activation through tPA knockout (tissue plasminogen activator, an essential element for microglia activation) leads to a delayed onset of the disease but increased severity and delayed recovery from the neurological dysfunction, which suggests that microglial activation is harmful during the onset of the disease but beneficial in the recovery phase [157] . Furthermore, when microglial activation was either stimulated or inhibited at different stages, the disease progression was attenuated or exacerbated accordingly [158] . For example, the inhibition of microglial activation at EAE onset, rather than prior to EAE induction, markedly decreased EAE progression, while the stimulation of microglial activation prior to the onset of EAE promotes lower-level EAE and an earlier recovery from symptoms. Together, these findings suggest different roles for microglial activation during various phases of the disease and that different timing of microglial activation dramatically affects whether microglia will be neuroprotective or deleterious [158] . Similarly, in an oxygen-glucose deprivation model, the time window of microglial neuroprotection has been estimated to up to 48 hour after injury, while the pre-stimulation of microglia with LPS before the injury fails to induce microglial-mediated neuroprotection [86] . It has been proposed that the effects of the early activation of microglia on disease progression could be beneficial through phagocytic activity and antigen presentation, recruitment and interactions with the adaptive immune response and the induction of protective autoimmunity [133] . Furthermore, the balance between protective autoimmunity and autoimmune disease may be determined by the timing and intensity of microglial activation [133] . As the immuno-competent cells in the CNS, microglia are critical determinants of the outcome of injury, and the timing of microglial activation appears to be crucial to the outcome of the injury. Thus, any interference with microglial activation in an attempt to affect the disease course clearly must be temporally-restricted.