Accumulated evidence points to GSK-3 as a critical intermediate in pro-apoptotic signaling cascades that are associated with neurodegenerative diseases, thus providing a potential target site amenable to pharmacological intervention (see Chapter 9 of this volume). Preliminary in vitro studies suggest potential neuroprotective effects of TDZDs against several insults, such as 6-OHDPA, lipopolysaccharide (LPS), stausporine-induced apoptosis, and glutamate. Pretreatment with TDZD-8 and lithium eliminate 6-OHDA neurotoxicity in a human dopaminergic neuronal cell line (SH-SY5Y) and in cultured rat cerebellar granule neurons (CGNs), indicating that GSK-3 is a key component of the proapoptotic signaling cascade .
TDZD-10 and TDZD-18 show neuroprotective activity in primary cortical neurons. These compounds protect cortical neurons from apoptosis induced by the cell-free medium from LPS-activated microglial cultures. In addition TDZDs protected cortical neurons against staurosporine-induced apoptosis and glutamate-induced excitotoxicity, suggesting that these compounds are potent neuroprotective agents against a wide variety of neuronal insults . Neuroprotection by TDZDs was coincident with a decrease in cytokine, COX-2, and iNOS expression as well as NO production. Accumulating data indicate that in addition to glial cells, neurons can express iNOS , which can produce the neurotoxic NO .
The effects of TDZDs on neuroprotection and inhibition of glial activation by LPS stimulation could be mediated by activation of the PPARy nuclear factor. In fact TDZD-10 and TDZD-18 can activate a reporter construct containing consensus PPARy binding sites, and this activation is further enhanced by 9-a's-RA, behavior characteristic of a classical PPARy/ RXR permissive heterodimer . Moreover the neuroprotective effects of these TDZDs are suppressed by GW9662, a specific antagonist of PPARy.
Collectively, these results indicate that TDZDs can be very effective neuroprotective and anti-inflammatory compounds in neuronal cells through, at least in part, activation of the nuclear receptor PPARy. This study suggests possible therapeutic uses for TDZDs in certain brain disorders, such as multiple sclerosis, as well as Parkinson's and Alzheimer's diseases, where inflammatory responses play a major role.
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