Neurotrophic Natural Products: Chemistry and Biology

Angew Chem Int Ed Engl, 2014 · DOI: 10.1002/anie.201302268 · Published: January 20, 2014

Simple Explanation

Neurodegenerative diseases affect millions and cost billions annually. Neurotrophins show promise for nerve regeneration, but have limitations. Small molecules with neurotrophic activity from natural sources present a promising alternative. This review focuses on natural products that boost neuronal growth and recovery, detailing synthesis approaches and biological effects. These natural products can serve as drug design templates. These compounds can also be used as tools to study the brain activity map project.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
Lactacystin, the first nonprotein neurotrophic natural product, exhibits neuritogenic activity and affects cell morphology and intracellular cAMP levels, impacting microtubule assembly and protein synthesis.
2
Illicium sesquiterpenes, including merrilactone A and jiadifenin, promote neurite outgrowth at nanomolar to micromolar concentrations in primary cultures of cortical neurons.
3
Huperzine A, a Lycopodium alkaloid, inhibits acetylcholinesterase, crosses the blood-brain barrier, prevents oxidative damage, increases NGF production, and promotes hippocampal neurogenesis.

Research Summary

Natural products are privileged structures that can lead to the development of new medicines and serve as tools in chemical biology for characterizing cell signaling pathways and evaluating biological events. Drug development approaches based on neurotrophins have encountered problems with oral availability, insufficient delivery to the brain, and high manufacturing cost. Synthetic strategies reviewed offer confidence that the privileged motifs of various neurotrophic natural products can be constructed in the laboratory, and advances in synthetic methods promise to improve these strategies.

Practical Implications

Drug Development

Neurotrophic natural products offer a promising avenue for developing new drugs to treat neurodegenerative diseases and spinal cord injuries, potentially overcoming limitations associated with protein-based therapeutics.

Chemical Biology Tools

These natural products can serve as valuable tools in chemical biology for developing new bioassays, characterizing cell signaling pathways, and chemically evaluating biological events related to neuronal growth and rehabilitation.

Brain Activity Map Project

Chemical neurotrophins are expected to play a critical role in the chemical evaluation of neural circuit remodeling, cognitive functions, and behavior within the context of the Brain Activity Map project.

Study Limitations

1
Chemical biology of neurotrophic natural products has not been explored methodically.
2
Complexity of pathways accounting for neural degeneration and the difficulties related to conducting biological experiments in primary neural cells.
3
Preventive approaches against neurodegeneration require consideration of various genetic and epidemiological studies that are not easy to correlate.

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