Anti-VPA monoclonal antibody, clone A803

Modulation of gamma-aminobutyric acid (GABA) levels has been required in various disorders. GABA itself cannot be directly introduced into central nervous system (CNS) because of the blood brain barrier; inhibition of GABA aminotransferase (GABA-AT), which degrades GABA in CNS, has been the target for the modulation of GABA levels in CNS. Given that root extract of valerian (Valeriana officinalis)has been used for millennia as anti-anxiolytic and sedative, in silico approach was carried out to investigate valerian compounds exhibiting GABA-AT inhibiting activity. The 3D structure of human GABA-AT was created from pig crystal structure via homology modeling. Inhibition of GABA-AT by 18 valerian compounds was analyzed using molecular docking and molecular dynamics simulations and compared with known GABA-AT inhibitors such as vigabatrin and valproic acid. Isovaleric acid and didrovaltrate exhibited GABA-AT inhibiting activity in computational analysis, albeit less potent compared with vigabatrin. However, multiple compounds with low activity may have additive effects when the total extract of valeriana root was used in traditional usage. In addition, isovaleric acid shares similar backbone structure to GABA, suggesting that isovaleric acid might be a valuable starting structure for the development of more efficient GABA-AT inhibitors for disorders related with low level of GABA in the CNS.

Background: Spinal cord injury (SCI) tends to damage neural tissue and generate a hypoxic environment. Studies have confirmed that single therapy with gene or stem cells is inefficient, but research into combining stem cells and gene therapy in treating tissue damage has been undertaken to overcome the related limitations, which include low gene delivery efficiency and therapeutic outcome. Thus, a combination of stem cells, gene therapy, and a hypoxia-specific system may be useful for the reconstruction of SCI. Methods: To synergistically treat SCI, a combined platform using a hypoxia/neuron-inducible gene expression system (HMS) and human induced-neural stem cells (hiNSCs) produced by direct reprogramming was designed. Sox2- or nestin-positive hiNSCs were differentiated to Tuj1-, MAP2-, or NeuN-positive neurons. Results: HNIS showed consistent hypoxia/neuron-specific gene expression in hiNSCs cultured under hypoxia. In particular, the HNIS-hiNSC combined platform revealed a complex pattern with higher gene expression compared with a single platform. In addition, we found that an optimal combination of small molecules, such as CHIR99021, valproic acid (VPA), glycogen synthase kinase-3 beta (GSK3 beta), and histone deacetylase (HDAC) inhibitors, could significantly enhance gene expression with HNIS-hiNSCs in the hypoxic environment. Conclusions: This experiment demonstrated that HNIS -hiNSCs combined with GSK3 and HDAC inhibitors may present another promising strategy in the treatment of SCI.