Neuroprotectants

Enhancing neuronal survival via the use of trophic agents, the majority of which are proteins, has been challenging as the latter do not readily cross the blood-brain barrier. The identification of small molecule neutrophin receptor agonists has also been challenging. Alternate strategies to target neurotrophic pathways involve the identification of: (1) NCEs that enhance neurotrophic protein production, e.g., propentofylline and SR-57746; and (2) small molecule peptide agonists that can be delivered intranasally, e.g., AL-108. Despite their preclinical efficacy, these neuroprotective agents have had limited clinical success.

6.08.2.7.14.1 Propentofylline

Propentofylline (50: HWA 285) is a xanthine phosphodiesterase inhibitor with weak adenosine uptake inhibitory properties that can potently stimulate astrocyte NGF synthesis. It partially restores age-associated decreases in cortical NGF in vivo and attenuates bilateral forebrain-induced impairments in animal behavioral tasks, and can also inhibit advanced glycation end-product-induced TNF-a release.

Propentofylline reduces Ab plaque burden and attenuated tau hyperphosphorylation in transgenic mice overexpressing APP with familial AD mutations.60 Two European phase III trials showed positive outcomes of propentofylline in AD but a longer-term 72-week trial failed to show benefit, and development was discontinued.

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