PTI - 125
Mechanisms of action
Aβ42 binds to the a7-nicotinic acetylcholine receptor (α7nAChR) with high affinity and initiate a toxic signaling cascade that phosphorylates tau and leads to the formation of neurofibrillary tangles. Aβ42 signaling via α7nAChR requires the recruitment of the scaffolding protein, filamin A (FLNA).
PTI-125 targets a specific novel site on FLNA and prevents FLNA - α7nAChR association and hence Aβ42’s toxic signaling. Additionally, PTI-125 provides an anti-inflammatory effect by avoiding the toll-like receptor 4 (TLR4) recruitment and this decreases TLR4 signaling and inflammatory cytokine release.
PTI-125 targets a specific novel site on FLNA and prevents FLNA - α7nAChR association and hence Aβ42’s toxic signaling. Additionally, PTI-125 provides an anti-inflammatory effect by avoiding the toll-like receptor 4 (TLR4) recruitment and this decreases TLR4 signaling and inflammatory cytokine release.
Study conducted - Wang et al. (2012)
In this recent study, PTI-125 showed effectiveness in mouse models of AD and in vitro brain tissues of patients that suffered from AD. The human data are too complicated to be explained, and therefore we will only go through the mice data in great details.
Immunohistochemistry in mice brains showed that PTI-125 significantly reduced neurofibrillary tangle (NFT) formation and Aβ42 deposition (Figure 1A). PTI-125 also reduced the levels of Aβ42 - α7nAChR complexes, illustrating its ability to dissociate bound Aβ42 (Figure 1B).
Immunohistochemistry in mice brains showed that PTI-125 significantly reduced neurofibrillary tangle (NFT) formation and Aβ42 deposition (Figure 1A). PTI-125 also reduced the levels of Aβ42 - α7nAChR complexes, illustrating its ability to dissociate bound Aβ42 (Figure 1B).
Figure 1: A)PTI-125 treatment and NFT immunoreactivity in both prefrontal cortex and hippocampus of mice receiving Aβ42 infusions. Significance was observed in the PTI-125 treated mice as compared to the untreated ones (P < 0.05). B) Aβ42 deposits in both brain regions of Aβ42-infused mice. Significance was observed between the PTI-125 treated and the untreated mice (P < 0.05).
Sham = control without Aβ42-infusion.
PTI-125 treatment inhibited the Aβ42-induced IL-6 production by 100%, TNF- α production by 86% and IL-1β production by 80% (Figure 2).
Evaluation
Is it novel and how?
Yes. This study presents a new target to prevent neuronal damages caused by Aβ formation and it is actually the first published study on PTI-125. Moreover, the fact that it only appeared on the news recently shows that it is novel.
Is it truly a medical breakthrough?
Yes. PTI-125 could lead to the development of a new drug that can reduce Aβ 42 deposition, neurofibrillary tangle formation and toxic immunological reaction due to amyloid plaques deposition. Besides, PTI-125 has helped to clarify the mechanisms of neurotoxicity involved in the amyloid plaques deposition in the neuronal tissues. For now, there are no in vivo PTI-125 data in humans, but it seems to be orally available and its action in animal models and in in vitro human brain tissues show that this is a promising AD treatment.
Difficulties that prevent it from being a new treatment
As only one study is currently available, more data are required for further drug development. Again, as the BACE inhibitors, PTI-125 cannot reverse any neuronal damages that have already existed, but they can slow down the progression of the disease. In other words, the agent is only useful in the earlier stages of the disease.
Copyright ©2012 by SW Wong, E Lo and N Rodrigues. All rights reserved.
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