Microneurotrophin BNN27 Reduces Astrogliosis and Increases Density of Neurons and Implanted Neural Stem Cell-Derived Cells after Spinal Cord Injury

Abstract

Microneurotrophins, small-molecule mimetics of endogenous neurotrophins, have demonstrated significant therapeutic effects on various animal models of neurological diseases. Nevertheless, their effects on central nervous system injuries remain unknown. Herein, we evaluate the effects of microneurotrophin BNN27, an NGF analog, in the mouse dorsal column crush spinal cord injury (SCI) model. BNN27 was delivered systemically either by itself or combined with neural stem cell (NSC)-seeded collagen-based scaffold grafts, demonstrated recently to improve locomotion performance in the same SCI model. Data validate the ability of NSC-seeded grafts to enhance locomotion recovery, neuronal cell integration with surrounding tissues, axonal elongation and angiogenesis. Our findings also show that systemic administration of BNN27 significantly reduced astrogliosis and increased neuron density in mice SCI lesion sites at 12 weeks post injury. Furthermore, when BNN27 administration was combined with NSC-seeded PCS grafts, BNN27 increased the density of survived implanted NSC-derived cells, possibly addressing a major challenge of NSC-based SCI treatments. In conclusion, this study provides evidence that small-molecule mimetics of endogenous neurotrophins can contribute to effective combinatorial treatments for SCI, by simultaneously regulating key events of SCI and supporting grafted cell therapies in the lesion site.

Multimodal beneficial effects of BNN27, a Nerve Growth Factor synthetic mimetic, in the 5xFAD mouse model of Alzheimer’s Disease

“…In addition, we have developed and patented synthetic C17derivatives of DHEA (named BNNs) (Calogeropoulou et al, 2009), shown to interact with NGF receptors, which are deprived of any harmful estrogenic or androgenic effects, in contrast to endogenous DHEA. BNN27, as the prototype member of these synthetic analogs for neurotrophins, has been extensively studied at the molecular level for its ability to selectively activate TrkA and p75NTR receptors, exerting strong neuroprotective effects mediated by the TrkA and p75NTR receptors in cell models of neurotoxicity and neurodegeneration (Pediaditakis et al, 2016b) as well as in in vivo models of diabetic retinopathy (Iban-Arias, 2018), demyelination (Bonetto, 2017), apomorhine-induced cognitive decline (Pitsikas et al, 2021) and spinal cord injury (Georgelou et al, 2023). In the present study, we sought to investigate whether BNN27 could mimic in vivo NGF actions against the AD phenotype and attenuate the well described AD-related neuropathology of the 5xFAD mice.…”

Combined Treatments and Therapies to Cure Spinal Cord Injury

“…Georgelou et al investigated the effects of a combined treatment involving the administration of small-molecule mimetics of endogenous neurotrophins and neural stem cells, demonstrating the synergistic effect of this combination in a mouse model of SCI by means of functional and histological studies [23].…”