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A major impediment for the clinical utility of neurotrophic factors is their inability to cross the blood-brain barrier in therapeutically significant amounts. Although several novel mechanisms for delivering exogenous neurotrophins to the brain have been developed, most of them involve invasive procedures or present significant risks. One approach to circumventing these problems is using therapeutic agents that can be administered systemically and have the ability to enhance the activity of neurotrophic factors. This review highlights the use of gangliosides, substituted pyrimidines, and mesenchymal stem cells as neurotrophic enhancers that have significant therapeutic potential while avoiding the pitfalls of delivering exogenous neurotrophic factors through the blood-brain barrier. 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