Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain.

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

Steroid-responsive intracranial germinoma presenting as Holmes' tremor: importance of a tissue diagnosis.

Holmes' tremor (rubral or midbrain outflow tremor) refers to a hyperkinetic movement disorder characterized by mild resting and more severe postural and action tremor often with associated brainstem symptoms, dystonia and cerebellar deficits. This syndrome should prompt lesional evaluation with neuroimaging focused on the dorsal midbrain, cerebellar outflow tracts, and thalamus. Herein we report a 26-year-old previously healthy male who presented with 4 years of progressive horizontal diplopia, right Parinaud syndrome, and appendicular ataxia. Neuroimaging revealed a right dorsal midbrain enhancing lesion which completely resolved with intravenous methylprednisolone prompting a diagnosis of neuroinflammatory syndrome. Subsequent clinical and radiographic evaluations, however, revealed steadily progressive left dorsal midbrain syndrome with an expansile enhancing lesion which culminated 4 years from symptom onset with a right upper extremity low-frequency rest, postural and action tremor, ataxic dysarthria, and mild right dystonia with dysdiadochokinesia. Uncomplicated brainstem biopsy confirmed intracranial germinoma and the patient underwent definitive radiation therapy with dramatic radiographic response and partial clinical improvement. This case, which to our knowledge is only the second report of intracranial germinoma presenting as Holmes' tremor, highlights the critical importance of definitive tissue diagnosis in the evaluation of lesional brainstem pathology presenting as Holmes' tremor. Steroid responsiveness can be seen in non-inflammatory pathology including intracranial germinoma. Prompt evaluation and appropriate treatment are important as Holmes' tremor responds poorly to symptomatic therapies and response to radiation therapy is favorable for germinomas.

A selective thyroid hormone ß receptor agonist enhances human and rodent oligodendrocyte differentiation.

Nerve conduction within the mammalian central nervous system is made efficient by oligodendrocyte-derived myelin. Historically, thyroid hormones have a well described role in regulating oligodendrocyte differentiation and myelination during development; however, it remains unclear which thyroid hormone receptors are required to drive these effects. This is a question with clinical relevance since nonspecific thyroid receptor stimulation can produce deleterious side-effects. Here we report that GC-1, a thyromimetic with selective thyroid receptor ß action and a potentially limited side-effect profile, promotes in vitro oligodendrogenesis from both rodent and human oligodendrocyte progenitor cells. In addition, we used in vivo genetic fate tracing of oligodendrocyte progenitor cells via PDGFαR-CreER;Rosa26-eYFP double-transgenic mice to examine the effect of GC-1 on cellular fate and find that treatment with GC-1 during developmental myelination promotes oligodendrogenesis within the corpus callosum, occipital cortex and optic nerve. GC-1 was also observed to enhance the expression of the myelin proteins MBP, CNP and MAG within the same regions. These results indicate that a ß receptor selective thyromimetic can enhance oligodendrocyte differentiation in vitro and during developmental myelination in vivo and warrants further study as a therapeutic agent for demyelinating models.

Granzyme B-induced neurotoxicity is mediated via activation of PAR-1 receptor and Kv1.3 channel.

Increasing evidence supports a critical role of T cells in neurodegeneration associated with acute and subacute brain inflammatory disorders. Granzyme B (GrB), released by activated T cells, is a cytotoxic proteinase which may induce perforin-independent neurotoxicity. Here, we studied the mechanism of perforin-independent GrB toxicity by treating primary cultured human neuronal cells with recombinant GrB. GrBactivated the protease-activated receptor (PAR)-1 receptor on the neuronal cell surface leading to decreased intracellular cyclic AMP levels. This was followed by increased expression and translocation of the voltage gated potassium channel, Kv1.3 to the neuronal cell membrane. Similar expression of Kv1.3 was also seen in neurons of the cerebral cortex adjacent to active inflammatory lesions in patients with multiple sclerosis. Kv1.3 expression was followed by activation of Notch-1 resulting in neurotoxicity. Blocking PAR-1, Kv1.3 or Notch-1 activation using specific pharmacological inhibitors or siRNAs prevented GrB-induced neurotoxicity. Furthermore, clofazimine protected against GrB-induced neurotoxicity in rat hippocampus, in vivo. These observations indicate that GrB released from T cells induced neurotoxicity by interacting with the membrane bound Gi-coupled PAR-1 receptor and subsequently activated Kv1.3 and Notch-1. These pathways provide novel targets to treat T cell-mediated neuroinflammatory disorders. Kv1.3 is of particular interest since it is expressed on the cell surface, only under pathological circumstances, and early in the cascade of events making it an attractive therapeutic target.

Antineuronal antibodies in OCD: comparisons in children with OCD-only, OCD+chronic tics and OCD+PANDAS.

Autoimmunity associated with a streptococcal infection has been proposed as a pathogenic mechanism for obsessive-compulsive disorder (OCD) in children. Antibrain antibody profiles were compared in children with OCD-only (n = 13; 14.1 +/- 3.1 years), OCD+PANDAS (n = 20; 11.3 +/- 1.5 years), OCD+Chronic Tic Disorder (n = 23; 13.4 +/- 3.5 years), and controls (n = 29; 12.4 +/- 2.4 years) using ELISA (orbitofrontal (OFC) and dorsolateral prefrontal cortex (DLPFC), caudate (CD), cingulate gyrus (CG)), immunoblotting (four regions plus putative antigens), and immunohistochemistry. ELISA and immunohistochemistry showed no differences among groups. Immunoblot showed that a greater percentage of individuals in the OCD+PANDAS cohort had reactive bands at 27 kDa (CD, CG, DLPFC), 36 kDa (CD), and 100 kDa (CD, OFC) and increased peak height at 67 kDa (all regions). Immunoblotting studies using the putative antigens (pyruvate kinase M1, aldolase C, alpha- and gamma-enolase) did not differ among groups. ASO titers were similar in all groups and did not correlate with immunoassays. It remains controversial whether childhood OCD is associated with autoimmune mechanisms.

Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls.

PANDAS and some cases of Tourette syndrome (TS) have been proposed to be post-streptococcal movement disorders in which antibodies produced against group A beta-hemolytic streptococcus cross react against brain epitopes. Attempts to identify disease specific anti-striatal antibodies in the serum of affected patients have focused on the use of Western immunoblotting and ELISA methodologies. In this study, immunohistochemical techniques were used to identify serum anti-striatal antibody reactivity. In positive samples, double staining with anti-GFAP (glial) and anti-MAP2 (neuronal) was used to establish localization of the immunofluorescence. No significant differences in immunofluorescence or localization were identified in patients with PANDAS (n=30) and TS (n=30) as compared to controls (n=30). IF reactivity did not correlate with tic severity or elevated titers of antistreptococcal antibodies. Further comparisons showed no correlation between autoreactivity determined by immunofluorescence and the presence of previously measured immunoblot reactivity against human caudate or putative antigens (pyruvate kinase M1 and aldolase C). These results confirm an inability to distinguish patient populations by antibody measurements and raise further concerns about the presence of an autoimmune mechanism in PANDAS and TS.