Anti-APP monoclonal antibody, clone 5F9

It is known that calpain activation is involved in human traumatic brain injury (TBI) and that calpain inhibition can have neuroprotective effects on both gray matter and white matter injury of TBI models. However, the role of calpain activation in the corpus callosum remains unclear and requires elucidation given its potential clinical relevance. We evaluated the neuroprotective effects of calpain inhibitor MDL-281-70 on corpus callosum function and structural destruction using a fluid percussion injury (FPI) model. The therapeutic time window for a single administration of MDL-28170 was up to 4 h post injury in protecting the corpus callosum structural integrity, and up to 30 min in protecting the axonal function evaluated 1 day following injury. When given 30 min prior injury, MDL-28170 showed neuroprotective effects that lasted up to 7 days. However, 30 min post injury administration of the drug afforded neuroprotection only up to 3 days. In contrast, two additional reinforcement injections at 24 and 48 h in addition to 30 min post FPI significantly protected both axonal function and structural integrity that lasted 14 days following FPI. Our data indicated that calpain inhibitor MDL-28170 is an effective neuroprotectant for axonal injury in corpus callosum following FPI with a therapeutic time window tip to 4 hours. Although delayed treatment (2 or 4 h post FPI) was effective in protecting the axonal structure, the axons saved may not be as functional as normal fibers. Multiple drug administrations may be necessary for achieving a persisting effectiveness of this compound.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder in the elderly. The current hypothesis for the cause of this disease is that it is the result of aberrant production of beta-amyloid (A beta) and plaque deposition in the brain. A beta(42), less soluble and forming the major component of the amyloid plaques, is generated via the cleavage of beta-amyloid protein precursor (beta-APP) by gamma-secretase, a key enzyme in the production of A beta. Therefore gamma-secretase is potential target for the treatment of Alzheimer's disease. This review focuses on the studies of the formation of A beta and the biology of gamma-secretase, and the development of gamma-secretase inhibitors.