Targeting macrophages by an aza-anthrapyrazole to ameliorate experimental autoimmune encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease in the central nerve system, in which both innate and adaptive immune cells are involved. BBR3378, an aza-anthrapyrazole prevents experimental autoimmune encephalomyelitis (EAE), an inflammatory condition similar to MS, by antagonizing T cell autoimmune responses. Here, we report BBR3378's regulatory effect on macrophages. METHODS: EAE was induced in ten-week-old female C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptides followed by BBR3378 or sham treatment administered intraperitoneally, and clinical signs were assessed using a 0-5 scoring system. These mice were subjected to serum ELISA for cytokine IFNγ and TNFα levels, RT qPCR analysis of macrophage markers in isolated monocytes, and flow cytometry analysis for macrophage infiltration in the brain. Macrophages derived from primary monocytes and macrophage cell line RAW 264.7 were used to investigate BBR3378's effect on LPS-stimulated pro-inflammatory cytokine induction. RAW 264.7 cells expressing NF-κB-driven luciferase reporter were treated with LPS with or without BBR3378, and luciferase assays performed to assess the inhibition on NF-κB activation. LPS-induced activation of mitogen-activated protein kinases (MAPKs) with or without the presence of BBR3378 was also investigated by Western blot analysis. RESULTS: BBR3378 down-regulated cytokine-induced macrophage differentiation and activation in EAE mice, contributing to protection against macrophage infiltration in the brain and clinical symptoms from EAE. Treating macrophages with BBR3378 counteracted LPS-induced cytokine production via blocking activation of key signal molecules mediating inflammatory responses, such as NF-κB and MAPKs. CONCLUSIONS: These data suggest that in addition to T cells, BBR3378 can also target macrophages to attenuate the inflammation associated with EAE.

Prevalence of autonomic dysfunction in hospitalized patients with Guillain-Barré syndrome.

INTRODUCTION: There is a paucity of data regarding autonomic dysfunction (AD) in Guillain-Barré Syndrome (GBS). Concern exists regarding inpatient mortality risk in GBS. We sought to identify the prevalence of AD in GBS inpatients. METHODS: We used the Health Cost and Utilization Project Nationwide Inpatient Sample (NIS). GBS hospitalizations were identified by International Classification of Diseases, Ninth Revision, Clinical Modification code-357.0. Non-GBS hospitalizations were matched to these cases 4:1 by age and gender. RESULTS: We identified 2,587 GBS patients and a control population of 10,348 patients during 2010-2011. The most common manifestations of AD were: diarrhea/constipation (15.5%), hyponatremia (14.9%), syndrome of inappropriate antidiuretic hormone secretion (SIADH) (4.8%), bradycardia (4.7%), and urinary retention (3.9%). GBS patients had higher rates of reversible cardiomyopathy, syncope, tachycardia, and Horner syndrome (P < 0.0001). CONCLUSIONS: AD most commonly manifests as diarrhea/constipation, SIADH/hyponatremia, and cardiac dysfunction. This report can help increase awareness of AD in GBS and aid in early identification, treatment, and mortality reduction. Muscle Nerve 56: 331-333, 2017.

Something Old, New, Borrowed, Blue: Anthracenedione Agents for Treatment of Multiple Sclerosis.

OBJECTIVE: This study aimed to present anthracenedione agents that have been used to treat multiple sclerosis (MS), problems related to their use, and knowledge gained from our experiences using these agents to develop more efficacious drugs with fewer adverse effects. METHODS: We review preclinical and clinical data during the development mitoxantrone, an anthracycline, for the treatment of MS; benefits and potential risks; and strategies to reduce complications of anthracyclines. RESULTS: Mitoxantrone had unacceptable and greater-than-anticipated toxicity for use in a chronic disease such as MS. Adverse effects included cardiotoxicity, treatment-associated leukemia, and amenorrhea. Toxicity was identified primarily in retrospect. Structurally related compounds include pixantrone (BBR2278) and BBR3378. Pixantrone is in clinical development in oncology. BBR3378 prevents the development of autoimmunity and experimental autoimmune encephalomyelitis and blocks experimental autoimmune encephalomyelitis even when given after the onset of autoimmunity. CONCLUSIONS: There remains a need for effective MS treatment, particularly for nonrelapsing forms of MS. Mitoxantrone was the first nonbiologic drug approved by the Food and Drug Administration for use in MS. Chromophore modification of anthracenedione agents yielded a novel class of DNA binding agents (aza-anthracenediones such as pixantrone and aza-anthrapyrazoles such as BBR3378) with the potential for less cardiotoxicity compared with mitoxantrone. There is a need for long-term observation for delayed toxicity among humans enrolled in pixantrone trials. Preclinical toxicity studies for delayed toxicities in rodents and other models are warranted before consideration of derivatives of anthracenediones, aza-anthrazenediones, or aza-anthrapyrazoles for use in human MS clinical trials.

Impact of oral health in patients with multiple sclerosis and epilepsy: a survey in a neurology clinic.

This study investigated the impact of oral health on neurological disorders using the Oral Health Impact Profile (OHIP). A total of 460 subjects completed the OHIP, including 141 control subjects who did not have any neurological conditions. Of the 319 subjects with a neurological diagnosis who were enrolled in the study, 31% had multiple sclerosis (MS), 34% had epilepsy, and 34% had other neurological conditions. Compared to the control group, mean age (p = .001), education (p = .003), and household income levels (p ≤ .001) were statistically significantly lower among subjects with epilepsy than in the other two groups. The majority of the study populations were Caucasian and the percentage was highest in those with MS (87%). Patients with any neurologic diagnosis had greater physical pain and disability than controls. Adjusting for demographic variables, the impact of physical disability was statistically significantly higher in patients with any neurological diagnosis (including MS and epilepsy) (OR = 4.49). In multinomial regression, the strongest association of physical disability impact was noted in patients with epilepsy (OR = 5.17). The physical disability domain of the OHIP is more commonly associated with a neurological diagnosis, including MS, and the association is strongest in patients with diagnosis of epilepsy.

Varying clinical presentations of familial cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs).

We present a family afflicted by both extensive cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs). These may be inherited in an autosomal dominant pattern or occur sporadically. The presentation varies and may include a multitude of clinical symptoms separated in time and space. Cavernous malformations should be considered in the differential diagnosis of such entities as stroke, headache, multiple sclerosis, and new-onset seizures after an intraparenchymal hemorrhage.

Neurologic complications after surgery for obesity.

Bariatric surgical procedures are increasingly common. In this review, we characterize the neurologic complications of such procedures, including their mechanisms, frequency, and prognosis. Literature review yielded 50 case reports of 96 patients with neurologic symptoms after bariatric procedures. The most common presentations were peripheral neuropathy in 60 (62%) and encephalopathy in 30 (31%). Among the 60 patients with peripheral neuropathy, 40 (67%) had a polyneuropathy and 18 (30%) had mononeuropathies, which included 17 (94%) with meralgia paresthetica and 1 with foot drop. Neurologic emergencies including Wernicke's encephalopathy, rhabdomyolysis, and Guillain-Barré syndrome were also reported. In 18 surgical series reported between 1976 and 2004, 133 of 9996 patients (1.3%) were recognized to have neurologic complications (range: 0.08-16%). The only prospective study reported a neurologic complication rate of 4.6%, and a controlled retrospective study identified 16% of patients with peripheral neuropathy. There is evidence to suggest a role for inflammation or an immunologic mechanism in neuropathy after gastric bypass. Micronutrient deficiencies following gastric bypass were evaluated in 957 patients in 8 reports. A total of 236 (25%) had vitamin B(12) deficiency and 11 (1%) had thiamine deficiency. Routine monitoring of micronutrient levels and prompt recognition of neurological complications can reduce morbidity associated with these procedures.