(−)‐Phenserine tartrate (PhenT) as a treatment for traumatic brain injury

Abstract

Aim: Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely. Discussion:We review recent data indicating that the small molecular weight drug (−)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI-and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman. Conclusion:In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.

The State of The Art on Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease

“…It can be considered as a multi-target drug thanks to its ability to inhibit Aβ-aggregation and was used for the treatment of cognitive impairments induced by traumatic brain injury in mice. 63 , 64 Phenserine was also tested in Phase II studies with moderate success. 65 Indeed, patients treated with phenserine (10 and 15 mg) versus placebo for 12 weeks showed a significative improvement of cognitive functions.…”

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

“…Along with the influence of patient age, central and peripheral sources of immune cells prominently contribute to secondary neurodegeneration during both the acute and chronic phases following stroke and TBI. [92][93][94][95][96][97] Indeed, neuroinflammation stands as the common denominator that accompanies both disease pathologies and closely parallels secondary neural cell loss throughout their progression. As such, elucidating the dynamic involvement of both central and peripheral sources, especially the interplay between the brain and the spleen, is key to understanding the mechanisms underlying neuroinflammation.…”

Traumatic brain injury

“…In a similar fashion, Greig and co‐investigators 9 reveal that the small molecular weight drug (‐)‐phenserine tartrate (PhenT), originally developed for Alzheimer's disease, effectively abrogates mild and moderate TBI via mitigation of multiple components of programmed neuronal cell death, including oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury‐induced gene pathways leading to chronic neurodegeneration. Both PGE 2 and PhenT treatments produced motor and cognitive improvements in TBI animals, 8,9 further increasing their clinical application potential.…”

“…The next two papers indeed advance novel drugs that encompass multiple targeting of cell death pathways. The paper by Dore and teammates demonstrate the potential of engaging the lipid metabolite prostaglandin E2 (PGE 2 ) as therapeutic targets to treat repetitive concussions and other acute brain injuries 8 . PGE 2 binding with the EP2 receptor activates adenylate cyclase and phosphorylates various cellular targets can lead to multiple neuroprotective processes, including anti‐inflammation.…”

“…The articles in this special issue probe the pathology of CNS trauma, including TBI and SIC, and begin to understand potential therapeutic modalities. Along this line, the proposed cell therapy 5‐7 and drug and immunization treatments 8‐10 offer new directions in the management of TBI. These promising therapies warrant serious consideration as we translate them into clinical applications.…”