Glia as a Therapeutic Target: Selective Suppression of Human Amyloid-β-Induced Upregulation of Brain Proinflammatory Cytokine Production Attenuates Neurodegeneration

Abstract

A corollary of the neuroinflammation hypothesis is that selective suppression of neurotoxic products produced by excessive glial activation will result in neuroprotection. We report here that daily oral administration to mice of the brain-penetrant compound 4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazine (MW01-5-188WH), a selective inhibitor of proinflammatory cytokine production by activated glia, suppressed the human amyloid-␤ (A␤) 1-42-induced upregulation of interleukin-1␤, tumor necrosis factor-␣, and S100B in the hippocampus. Suppression of neuroinflammation was accompanied by restoration of hippocampal synaptic dysfunction markers synaptophysin and postsynaptic density-95 back toward control levels. Consistent with the neuropathophysiological improvements, MW01-5-188WH therapy attenuated deficits in Y maze behavior, a hippocampal-linked task. Oral MW01-5-188WH therapy begun 3 weeks after initiation of intracerebroventricular infusion of human A␤ decreased the numbers of activated astrocytes and microglia and the cytokine levels in the hippocampus without modifying amyloid plaque burden or altering peripheral tissue cytokine upregulation in response to an in vivo inflammatory challenge. The results provide a novel integrative chemical biology proof in support of the neuroinflammation hypothesis of disease progression, demonstrate that neurodegeneration can be attenuated independently of plaque modulation by targeting innate brain proinflammatory cytokine responses, and indicate the feasibility of developing efficacious, safe, and selective therapies for neurodegenerative disorders by targeting key glial activation pathways.

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

“…The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the amyloidogenic Aβ 1-42 [18,76]. The view that neuroinflammation contributes directly to AD pathogenesis is consistent with recent observations showing that selective inhibition of proinflammatory cytokine production suppresses in the hippocampus the chronic Aβ infusion-induced decrease in synaptic markers and attenuates deficit in a hippocampuslinked memory task [56].In the healthy brain, the concentration of IL-1 is very low, but IL-1 is rapidly induced in response to injury. The increase in IL-1 after traumatic brain injury is followed by neuronal loss.…”

Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay between Proinflammatory and Anti-Inflammatory Signals

“…Glial cells are a rich source of trophic signals for neurons, and its potential use as therapeutic targets in neurodegenerative diseases has already been outlined (Ranaivo et al, 2006). However, a better knowledge of the pathways involved in glia-to-neuron protective communication is needed before we can properly address this goal.…”

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

“…22,23 Recent reports suggest that astrocytes can be an important target for the development of neuroprotective drugs. 24,25 Most of the previous studies concerning the neurotrophic and neuroprotective effects of VPA emphasize its direct neuronal effects and thus might have excluded the role of glial cells, particularly astrocytes. 26,27 The present study was undertaken to investigate the critical role of astrocytes in VPAinduced neurotrophic and neuroprotective effects and also the potential use of VPA for treating neurodegenerative disorders.…”