Effect of teriflunomide on cortex-basal ganglia-thalamus (CxBGTh) circuit glutamatergic dysregulation in the Theiler's Murine Encephalomyelitis Virus mouse model of multiple sclerosis.

BACKGROUND: Pathology of gray matter is associated with development of physical and cognitive disability in patients with multiple sclerosis. In particular, glutamatergic dysregulation in the cortex-basal ganglia-thalamus (CxBGTh) circuit could be associated with decline in these behaviors. OBJECTIVES: To investigate the effect of an immunomodulatory therapy (teriflunomide, Aubagio®) on changes of the CxBGTh loop in the Theiler's Murine Encephalomyelitis Virus, (TMEV) mouse model of MS. METHODS: Forty-eight (48) mice were infected with TMEV, treated with teriflunomide (24) or control vehicle (24) and followed for 39 weeks. Mice were examined with MRS and volumetric MRI scans (0, 8, 26, and 39 weeks) in the cortex, basal ganglia and thalamus, using a 9.4T scanner, and with behavioral tests (0, 4, 8, 12, 17, 26, and 39 weeks). Within conditions, MRI measures were compared between two time points by paired samples t-test and across multiple time points by repeated measures ANOVA (rmANOVA), and between conditions by independent samples t-test and rmANOVA, respectively. Data were considered as significant at the p<0.01 level and as a trend at p<0.05 level. RESULTS: In the thalamus, the teriflunomide arm exhibited trends toward decreased glutamate levels at 8 and 26 weeks compared to the control arm (p = 0.039 and p = 0.026), while the control arm exhibited a trend toward increased glutamate between 0 to 8 weeks (p = 0.045). In the basal ganglia, the teriflunomide arm exhibited a trend toward decreased glutamate earlier than the control arm, from 0 to 8 weeks (p = 0.011), resulting in decreased glutamate compared to the control arm at 8 weeks (p = 0.016). CONCLUSIONS: Teriflunomide may reduce possible excitotoxicity in the thalamus and basal ganglia by lowering glutamate levels.

Acute myelitis by human herpes virus 7 in an HIV-infected patient.

BACKGROUND: HHV7 reactivation has been occasionally reported as a cause of encephalitis or myelitis in transplant recipients, but to our knowledge it has never been associated with neurological disease in HIV-infected patients. We report a case of acute myelitis in an HIV-infected patient, with sustained HHV-7 DNA amplification in cerebrospinal fluid (CSF) and a favourable response to foscarnet. CASE REPORT: A 40 year-old man with HIV infection was admitted with asymmetric hypoesthesia in legs and paraparesis. He was receiving treatment with efavirenz, emtricitabine and tenofovir, his CD4 count was 580/mm3 and HIV viral load was undetectable. Magnetic resonance imaging showed a focal central hyperintensity on T2 and STIR sequences, on the torathic spinal cord, with slight enhancement after intravenous gadolinium. All microbiological studies were negative except for HHV-7 DNA amplification in CSF. With a diagnosis of idiopathic transverse myelitis, treatment with high-dose intravenous methylprednisolone was initiated. However, paraparesis continued worsening, and a second CSF obtained 12 days after the first one resulted again in HHV-7 amplification. RESULTS: The patient was treated with a 2 week course of foscarnet, and a rapid neurological improvement was noted. After treatment, PCR for HHV-7 in CSF was negative. Neurological exam was normal one month after treatment initiation. CONCLUSION: HHV-7 reactivation may cause neurological disease in patients with HIV infection. Foscarnet is an effective treatment in HHV-7 associated myelitis.

[An analysis of clinical and imaging characteristics of atopic myelitis].

OBJECTIVE: To study the clinical and imaging characteristics of Chinese atopic myelitis (AM) patients. METHODS: Three diagnosed AM patients were retrospectively analyzed for the clinical data, serum IgE level, antigen specific IgE, cerebrospinal fluid, spinal MRI and therapeutic efficacy profiles. RESULTS: All the three patients were male and presented as subacute AM with the onset at 25, 47 and 49 years old respectively. Two patients were allergic to pollen and other drugs, while another patient suffered from allergic rhinitis. Elevated serum total IgE and mite antigen specific IgE were found in all cases. Paraesthesia in limb extremities and positive Lhermitte sign were the main clinical features, while no optic, motor, urinary and defecation disturbance were found. Oligoclonal banding of cerebrospinal fluid and serum aquaporin 4 (AQP4) antibody were both negative in all cases. Spinal MRI showed lesions were hypointense on T1 and hyperintense on T2 at the posterior column of T2-3 segment with abnormal enhancement in case 1, hypointense on T1 and hyperintense on T2 at C2/3 segment with mild swelling in case 2 and hypointense on T1 and hyperintense on T2 at C3-5 segments with swelling and abnormal enhancement in case 3. Vitamin B were used in one patient, while the other two patients improved after the treatment with high-dose corticosteroids. CONCLUSIONS: Subacute myelitis predominantly presents as paraesthesia in limb extremities with elevated serum total IgE and mite antigen specific IgE, while severe motor disorders are rare. Swelling and abnormal enhancement lesions at the posterior column of cervical cord are the common imaging features. Treatment with corticosteroids is recommended to be sustained for 3-6 months.

Analgesic activity of catalpol in rodent models of neuropathic pain, and its spinal mechanism.

Neuropathic pain is a major health issue that represents considerable social and economic burden worldwidely. In this study, we investigated the potential of catalpol, an iridoid glucoside of Rehmannia glutinosa Steud, to alleviate neuropathic pain. The potential analgesic effects of catalpol were evaluated by chronic constriction injury (CCI) and lumbar 5 spinal nerve ligation (L5 SNL) model. In addition, we explored whether catalpol altered the degree of microglia activation and neuroinflammation in rat spinal cord after CCI induction. Repeated administration of catalpol (1, 5, 25, and 125 mg/kg) reversed mechanical allodynia induced by CCI and L5 SNL in a dose-dependent manner in rats. Levels of activated microglia, activated NF-κB, and proinflammatory cytokines (IL-1ß, IL-6, TNF-α) in lumber spinal cord were elevated in rats following CCI induction, and catalpol significantly inhibited these effects. Our results demonstrated that catalpol produces significant antinociceptive action in rodent behavioral models of neuropathic pain and that this effect is associated with modulation of neuroinflammation in spinal cord.

Neuroprotective effect of Scutellaria baicalensis on spinal cord injury in rats.

Inflammation has been known to play an important role in the pathogenesis after spinal cord injury (SCI). Microglia are activated after injury and produce a variety of proinflammatory factors such as tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, and reactive oxygen species leading to apoptosis of neurons and oligodendrocytes. In this study, we examined the neuroprotective effects of total ethanol extract of Scutellaria baicalensis (EESB), after SCI. Using primary microglial cultures, EESB treatment significantly inhibited lipopolysaccharide-induced expression of such inflammatory mediators as tumor necrosis factor-alpha, IL-1beta, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase. Furthermore, reactive oxygen species and nitric oxide production were significantly attenuated by EESB treatment. For in vivo study, rats that had received a moderate spinal cord contusion injury at T9 received EESB orally at a dose of 100 mg/kg. EESB inhibited expression of proinflammatory factors and protein carbonylation and nitration after SCI. EESB also inhibited microglial activation at 4 h after injury. Furthermore, EESB significantly inhibited apoptotic cell death of neurons and oligodendrocytes and improved functional recovery after SCI. Lesion cavity and myelin loss were also reduced following EESB treatment. Thus, our data suggest that EESB significantly improve functional recovery by inhibiting inflammation and oxidative stress after injury.

Erythropoietin in spinal cord injury.

Spinal cord injury (SCI) is a devastating condition for individual patients and costly for health care systems requiring significant long-term expenditures. Cytokine erythropoietin (EPO) is a glycoprotein mediating cytoprotection in a variety of tissues, including spinal cord, through activation of multiple signaling pathways. It has been reported that EPO exerts its beneficial effects by apoptosis blockage, reduction of inflammation, and restoration of vascular integrity. Neuronal regeneration has been also suggested. In the present review, the pathophysiology of SCI and the properties of endogenous or exogenously administered EPO are briefly described. Moreover, an attempt to present the current traumatic, ischemic and inflammatory animal models that mimic SCI is made. Currently, a clearly effective pharmacological treatment is lacking. It is highlighted that administration of EPO or other recently generated EPO analogues such as asialo-EPO and carbamylated-EPO demonstrate exceptional preclinical characteristics, rendering the evaluation of these tissue-protective agents imperative in human clinical trials.

Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS.

In amyotrophic lateral sclerosis (ALS), an involvement of the immune system in the degenerative processes has been shown in both humans and the transgenic SOD1-G93A mice. We previously showed that Glatiramer acetate (also known as copolymer-1; COP-1; Copaxone) improves motor function and extends survival times in an inbred strain of ALS mice probably by interacting with pro-inflammatory T(H) lymphocytes. In the course of this study we tested whether these beneficial effects could be reproduced by repeated vaccination of animals with COP-1 without co-administration of complete Freund's adjuvant. In an outbred strain we could not demonstrate a positive effect of COP-1 on survival times, but found a significant improvement of motor performance during the late stage of disease and a moderate decrease of the production of the inflammatory cytokines interferon-gamma and IL-4 by T lymphocytes isolated from the mice's spleen. In conclusion, the effects of COP-1 in the applied hybrid strain displaying a faster disease progression were less pronounced than in the earlier tested inbred strain of ALS mice.