Dimethyl fumarate mitigates optic neuritis.

Purpose: Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a demyelinating autoimmune disease characterized by acute episodes of motor, sensory, and cognitive symptoms. Optic neuritis is an episodic sequela experienced by some patients with RRMS that typically presents as acute, monocular vision loss. Episodes of optic neuritis damage and kill retinal ganglion cells (RGCs), and can culminate in permanent vision loss. The purpose of these studies was to evaluate the capacity of DMF to mitigate optic neuritis. The work presented combines studies of a mouse model of MS and a retrospective chart analysis of files of patients with RRMS treated at the MS Center of Excellence within the Oklahoma Medical Research Foundation. Methods: Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model that recapitulates cardinal features of somatic and visual MS pathologies. EAE was induced in female C57BL/6J mice by inoculation with myelin oligodendrocyte glycoprotein peptide (residues 35-55; MOG35-55). DMF or vehicle was administered twice a day by oral gavage. Visual acuity was measured longitudinally with optokinetic tracking. Post-mortem analyses included quantification of RGCs in retinal flatmounts and quantitative PCR (qPCR) of Nrf2 target genes and regulators of myelin. Retrospective chart analyses were performed using data obtained from deidentified files of patients with RRMS. Results: In the EAE mouse studies, DMF decreased optic neuritis severity, preserved vision and RGCs, and concomitantly reduced motor deficits when administered by two different treatment regimens (prevention or interventional). DMF was more efficacious when administered as an interventional therapy, and the beneficial effects occurred independently of the induction of Nrf2 target genes. A complementary retrospective chart analysis demonstrated that DMF increased the time to a recurrence of optic neuritis, and protected against subsequent bouts of optic neuritis. Conclusions: This work underscores the potential of DMF to mitigate the severity and recurrence of optic neuritis episodes in patients with RRMS.

Characterization of medial septal glutamatergic neurons and their projection to the hippocampus.

The two neuronal populations that have been typically investigated in the septum use acetylcholine and GABA as neurotransmitters. The existence of noncholinergic, non-GABAergic, most likely glutamatergic septal neurons has recently been reported. However, their morphological characteristics, numbers, distribution, and connectivity have not been determined. Furthermore, the projection of septal glutamatergic neurons to the hippocampus has not been characterized. To address these issues, subpopulations of cholinergic and GABAergic neurons were identified by immunohistochemistry. In addition, the retrograde tracer fluorogold was injected into the hippocampus to determine the characteristics of a glutamatergic septo-hippocampal projection. Our work revealed that although glutamatergic neurons are found throughout the septum, they concentrate in medial septal regions. Using stereological probes, approximately 16,000 glutamatergic neurons were estimated in the medial septal region. Triple immunostaining showed that most glutamatergic neurons do not immunoreact with cholinergic or GABAergic neuronal markers (anti-ChAT or anti-GAD67 antibodies, respectively). Fluorogold injections into CA1, CA3, and dentate gyrus of the hippocampus showed that septal glutamatergic neurons project to each of these hippocampal regions, forming approximately 23% of the septo-hippocampal projection. Most cell bodies of septo-hippocampal glutamatergic neurons were located in the medial septum. The remaining cell bodies were found in the diagonal band. This data shows that glutamatergic neurons constitute a significant neuronal population in the septum and that a subpopulation of these neurons projects to hippocampal regions. Thus, the septo-hippocampal projection needs to be reconsidered as a three neurotransmitter pathway.

Glutamic acid decarboxylase isoforms are differentially distributed in the septal region of the rat.

The septal region of the brain consists of a heterogeneous population of GABAergic neurons that play an important role in the generation of hippocampal theta rhythms. While GABAergic neurons employ two isoforms of the enzyme glutamic acid decarboxylase (GAD) for the synthesis of GABA, distribution of GAD isoforms has not been investigated in the septum. Immunohistochemical techniques were used to investigate the expression of GAD enzymes in medial and lateral septum. GAD65 and GAD67 immunohistochemistry revealed dense fibers and punctuated immunoreactivity in septal regions. While few GAD65-positive neuronal somas were detected in medial septum, a significantly higher number of immunoreactive neurons were detected in lateral septum. GAD65- and GAD67-positive neurons in the lateral septum exhibit higher complexity of dendritic arborizations than in the medial septum where staining was mainly restricted to the soma. Presumptive axon terminals (puncta) showed abundant immunoreactivity predominantly for GAD65 isoforms in all septal regions. This suggests that septal GABAergic neurons differentially express GAD enzymes thereby potentially reflecting functional differences. Differences found between medial and lateral septal GABAergic neuronal populations are in agreement with the concept that medial and lateral septum are brain structures with highly different connectivity and function despite anatomical proximity.