Air bubble after intrathecal triamcinolone acetonide application in a progressive multiple sclerosis patient

Repeated intrathecal application of the sustained release steroid Triamcinolone Acetonide (TCA) is beneficial in progressive Multiple Sclerosis (MS) patients [1]. Particularly, patients with spinal lesions often show a distinct benefit with a three fold increase of the maximum walking distance [2]. This therapy ameliorates walking distance, improves upper limb function and reduces spastic symptoms [1]. The putative regenerative effect may result from declined synthesis of the repulsive guidance molecule A [3]. Visualization of air bubbles after a TCA injection prompted this case report.

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

Symptomatic treatments are available for Parkinson’s disease and Alzheimer’s disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.

Inhibition of repulsive guidance molecule-a protects dopaminergic neurons in a mouse model of Parkinson’s disease

Repulsive guidance molecule-a (RGMa), a glycosylphosphatidylinositol-anchored membrane protein, has diverse functions in axon guidance, cell patterning, and cell survival. Inhibition of RGMa attenuates pathological dysfunction in animal models of central nervous system (CNS) diseases including spinal cord injury, multiple sclerosis, and neuromyelitis optica. Here, we examined whether antibody-based inhibition of RGMa had therapeutic effects in a mouse model of Parkinson’s disease (PD). We treated mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and found increased RGMa expression in the substantia nigra (SN). Intraventricular, as well as intravenous, administration of anti-RGMa antibodies reduced the loss of tyrosine hydroxylase (TH)-positive neurons and accumulation of Iba1-positive microglia/macrophages in the SN of MPTP-treated mice. Selective expression of RGMa in TH-positive neurons in the SN-induced neuronal loss/degeneration and inflammation, resulting in a progressive movement disorder. The pathogenic effects of RGMa overexpression were attenuated by treatment with minocycline, which inhibits microglia and macrophage activation. Increased RGMa expression upregulated pro-inflammatory cytokine expression in microglia. Our observations suggest that the upregulation of RGMa is associated with the PD pathology; furthermore, inhibitory RGMa antibodies are a potential therapeutic option.

Repulsive Guidance Molecule A Regulates Adult Neurogenesis Via the Neogenin Receptor

Repulsive guidance molecule A (RGMa) exhibits repulsive guidance of axonal growth and regulates neuronal differentiation during development of the mammalian brain. In this commentary, we describe the findings of our recent paper, “Repulsive Guidance Molecule A Suppresses Adult Neurogenesis,” and discuss a possible model for RGMa suppression of newborn neurons that fail to properly migrate into the granular cell layer. In the study, we provided evidence that RGMa suppressed neurite growth and survival of newborn neurons in the adult dentate gyrus. This effect depends on the multifunctional Neogenin receptor expressed in adult neural stem cells through activation of the Rho-associated protein kinase leading to neurite growth inhibition and ultimately cell death. It should be noted that both RGMa and Neogenin interact with several well-described molecules, including bone morphogenetic proteins, that regulate neuronal development. Thus, it is likely that RGMa interacts with other intricate molecular networks that regulate adult neurogenesis.

Construction of Repulsive Guidance Molecule A-Specific RNA Interference Recombinant Adenovirus

This study aims to construct an RGMa RNAi plasmid in preparation for a subsequent research, and three shRNAs were designed for collection. The designed shRNAs were taken into the target plasmid of pegensil-1 to silence the mRNA of RGMa. Sequencing and enzyme identification were performed, and PC12 cells were transfected with a shRNA-containing plasmid. Then, the effect of the silencing of the gene was tested by RT-PCR using PC12 cells and to choose the best one. The results showed that the first one was choose for the subsequent research among these three designed shRNAs, which had the highest transfection efficiency and a concentration of 2.5 × 109 pfu/ml. The concentration of Adv(–) was 2.1 × 109 pfu/ml for the blank control. The effect of the constructed RGMa RNAi plasmid for the subsequent research is stable and effective.