| Currently, there is no effective medicine for the treatment of neurodegenerative diseases. Current therapeutic agents, including neurotrophic factors, are limited by several shortcomings such as blood brain barrier (BBB)-impermeability, side effects, and short half-life in the blood. During our search for an alternative that overcomes these shortcomings, we discovered that low acyl gellan gum and its cleavage product, midi-GAGR, have strong neuroprotective and neurotrophic properties. Since low acyl gellan gum has few side effects in humans and is biocompatible and relatively stable in the body, it has been used for food additive and medical application in humans. In our study, low acyl gellan gum and midi-GAGR not only enhanced neuritogenesis in neuron-like N2A cells and mouse primary cortical neurons, but also protected those cells from the oxidative insults of lipid and hydrogen peroxide and amyloid beta 42 peptide (cortical neurons). Low acyl gellan gum and midi-GAGR activated a neuron survival signaling pathway that increased the active form of cAMP response element-binding protein (CREB) in the nuclei of cortical neurons. Moreover, we confirmed the blood brain-permeability of midi-GAGR and its structural intactness in SD rats using a fluorescent tag, ANTS. Furthermore, brain-penetrating midi-GAGR maintained its neurotrophic effect for 24 h when administered intranasally into rats. In a peripheral nerve injury rat model, midi-GAGR encapsulated in peptide nanotubes enhanced neuro-regeneration following infraorbital nerve transection. Taken together, midi-GAGR with brain-permeability and strong neuroprotective and neurotrophic properties has promise as therapeutic agent for the treatment of neurodegenerative diseases. |
