Neurotrophic and Neuritogenic Drug Leads from Natural Products

Neuritogenesis or neuritic outgrowth is a fundamental cellular differentiation process for formation of new neurons. Recent reports have indicated importance of this process in neuroregeneration and repair of damaged neurons. Neurotrophic and neuritogenic substances, which repair damaged neurons through stimulation of neuritic outgrowth, may be important for restoration and readjustment of normal neuronal functions of the damaged neurons. Neurotrophins namely, Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotrophin-4 (NT-4), stimulate neuritogenesis through regulation of neural survival, development, function, and plasticity. The neurotrophins may have potential application in treatment of neuronal injuries and neurodegenerative diseases. However, inadequate or negligible penetration through blood brain barrier and susceptibility to degradation by the peripheral proteases prevent therapeutic application of endogeneous peptidic neurotrophins. The bioactive small molecules with neurotrophic and neuritogenic actions hold great promise as therapeutic agents for treatment of neurodegenerative diseases and neuronal injuries by virtue of their ability to stimulate neuritic outgrowth. Use of natural products eliciting neuritogenic activity alone or in combination with neurotrophic substances are currently being focused on as an important approach. In addition to this, other evidence shows that compounds capable of enhancing the action of neurotrophic factors to stimulate neurite outgrowth may be useful in the treatment of neurological disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Hence, identification of neuritogenic & neurotrophic molecules from natural sources may provide important drug leads for activation of neuroregeneration in various forms of neuronal injuries. Screening of natural compounds libraries for stimulation of neuritic outgrowth in in vitro cell-culture models have identified several neurotrophic and neuritogenic natural product substances. Neurotrophic tyrosine kinase receptor type 1 (Trk-A) is a membrane-bound high affinity nerve growth factor receptor that, upon neurotrophin binding, phosphorylates itself (autophosphorylation) and members of the MAPK pathway. Activation of Trk-A triggers a signal transductions cascade, which leads to cell differentiation and may play a role in specifying sensory neuron subtype. A transgenic cell line overexpressing TrkA receptor functions have provided an important tool for large scale screening of natural products libraries. Focused screening of a library of harmala alkaloids, selected cannabis constituents and other natural products has identified new natural products leads that produced significant activation of NGF-stimulated neuritic outgrowth. Further interrogations of the lead natural products through TrkA-A associated signal transduction pathways; histone deacetylases and cell-cycle associated functions have provided useful clues regarding mechanism for neuritogenic action. Similar approach have also been applied for screening a library of extracts prepared from the botanicals, which are traditionally known to improve brain functions, learning, memory and other neurological disorders.