Neurotrophic Neuroprotectant small molecules

Neurotrophic factor replacement strategies for ALS treatment have met with limited success to date; whether this is a result of short half-lives of proteins or an inability to cross the blood-brain barrier is not fully understood. However, preclinical data strongly support a role of these proteins in the maintenance of survival as well as rescue from a variety of toxic insults to motor neurons. To circumvent the potential issues of protein therapeutics in treating CNS disease, several alternate strategies have been taken either to enhance endogenous levels of neurotrophic proteins or to identify small molecules with neurotrophic-like properties. Xaliproden (SR-57746A 91) is a small-molecule, 5HT1A agonist that stimulates BDNF production in vitro and promotes motor neuron survival both in vitro and in vivo.98 In a double-blind Phase II study, patients taking xaliproden, as compared to those on placebo, who completed the 32-week study showed a slower rate of deterioration in vital capacity.99 However, two phase III trials failed to reach significance.100

Arimoclomol 92 amplifies the heat shock response by increasing the levels of heat shock proteins that have antiapoptotic properties.101 In the SOD-1 G93A ALS model, arimoclomol improved hindlimb muscle function and motor neuron survival and resulted in a 22% increase in lifespan. This NCE is proceeding to Phase II clinical trials.

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