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Intracerebroventricular kainate administration in rat, a model of temporal lobe epilepsy (TLE), causes degeneration of the hippocampal CA3 pyramidal and dentate hilar neurons. This leads to a robust but aberrant sprouting of the granule cell axons (mossy fibers) into the dentate supragranular layer and the CA3 stratum oriens. Because this plasticity is linked to an increased seizure susceptibility in TLE, strategies that restrain the aberrant mossy fiber sprouting (MFS) are perceived to be important for preventing the TLE development after the hippocampal injury. We ascertained the efficacy of fetal hippocampal CA3 or CA1 cell grafting into the kainate-lesioned CA3 region of the adult rat hippocampus at early post-kainic acid injury for providing a lasting inhibition of the aberrant MFS. Analyses at 12 months after grafting revealed that host mossy fibers project vigorously into CA3 cell grafts but avoid CA1 cell grafts. Consequently, in animals receiving CA3 cell grafts, the extent of aberrant MFS was minimal, in comparison with the robust MFS observed in both "lesion-only" animals and animals receiving CA1 cell grafts. Analyses of the graft axon growth revealed strong graft efferent projections into the dentate supragranular layer with CA3 cell grafting but not with CA1 cell grafting. Thus, the formation of reciprocal circuitry between the dentate granule cells and the grafted CA3 pyramidal neurons is likely the basis of inhibition of the aberrant MFS by CA3 cell grafts. The results also underscore that grafting of cells capable of differentiating into CA3 pyramidal neurons is highly efficacious for a lasting inhibition of the abnormal mossy fiber circuitry development in the injured hippocampus. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a complex debilitating condition leading to permanent life-long neurological deficits. Estrogen (E2) treatment is known to be neuroprotectant in SCI. This hormone is highly pleiotropic and has been shown to decrease apoptosis, modulate calcium signaling, regulate growth factor expression, act as an anti-inflammatory, and drive angiogenesis. These beneficial effects were found in our earlier study at the low dose of 10 µg/kg E2 in rats. However, the dose remains non-physiologic, which poses a safety hurdle for clinical use. Thus, we recently devised/constructed a fast release nanoparticle (NP) estrogen embedded (FNP-E2) construct and tested a focal delivery system in a contused SCI rat model which showed protection in the short run. In the current study, we have developed a novel slow-release NP estrogen (SNP-E2) delivery system that shows sustained release of E2 in the injured spinal cord and no systemic exposure in the host. The study of E2 release and kinetics of this SNP-E2 construct in vitro and in vivo supported this claim. Delivery of E2 to the injured spinal cord via this approach reduced inflammation and gliosis, and induced microglial differentiation of M1 to M2 in rats after SCI. Analysis of spinal cord samples showed improved myelination and survival signals (AKT) as demonstrated by western blot analysis. SNP-E2 treatment also induced astrocytic differentiation into neuron-like (MAP2/NeuN) cells, supported the survival of oligodendrocyte precursor cells (OPC), and improved bladder and locomotor function in rats following SCI. These data suggest that this novel delivery strategy of SNP-E2 to the injured spinal cord may provide a safe and effective therapeutic approach to treat individuals suffering from SCI., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)