Although folate deficiency was reported to be associated with hyperhomocysteinemia, influence of folate supplementation on cognition remains controversial. Therefore, we explored the effects of folate supplementation on the cognition and Homocysteine (Hcy) level in relatively short periods in patients with folate deficiency and cognitive impairment. Enrolled 45 patients (mean age of 79.7 ± 7.9 years old) with folate deficiency (<3.6 ng/mL) with cognitive impairment underwent Mini-Mental State Examination (MMSE), and laboratory examinations, including folate, vitamin B12, and Hcy. The degree of hippocampal atrophy in MRI was estimated using a voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD). Patients were administrated folate (5 mg/day), then Hcy, and MMSE score were re-examined after 28 to 63 days. Mean Hcy significantly decreased from 25.0 ± 18.0 to 11.0 ± 4.3 nmol/mL (p < 0.001). Average MMSE scores also significantly changed from 20.1 ± 4.7 to 22.2 ± 4.3 (p < 0.001). The degree of change in the MMSE score and basic Hcy or Hcy change was significantly positively correlated, while degree of hippocampal atrophy in MRI did not. Although several factors should be taken into account, folate supplementation ameliorated cognitive impairment, at least for a short period, in patients with folate deficiency.
. Abbreviations: BALF = bronchoalveolar lavage fluid; IFN = interferon; IL = interleukin; i.n. = intranasal; MAb(s) = monoclonal antibody(ies); p.i. = post infection; TNF = tumor necrosis factor Interleukin 12 is a primary cytokine responding to influenza virus infection in the respiratory tract of mice Summary. -We have reported previously that an increase in interleukin 12 (IL-12) production in the lungs of mice infected with Influenza A virus or an intranasal (i.n.) administration of IL-12 to the infected mice alleviated pneumonia (Tsurita et al., J. Pharmacol. Exp. Therapeut. 298, 362-368, 2001). In this study, we found that in the bronchoalveolar lavage fluids (BALF) obtained from mice infected i.n. with Influenza A virus IL-12 was elevated on day 1 post infection (p.i.) and was followed by tumor necrosis factor α (TNF-α), IL-18, and interferons α, β, and γ (IFN-α, -β, and -γ) on day 2 p.i. Histochemical analyses of the infected lungs on day 1 p.i. showed the presence of IL-12 and IL-12 mRNA in mononuclear and macrophage-like cells and colocalization of macrophages with viral antigen, while other cytokines were absent. Thus, IL-12 was produced by macrophages infiltrating the infected epithelium as the first response cytokine and its production at the site of infection may direct an early immune defense to alleviate the severity of infection.
Varicella-zoster virus (VZV) expresses immediate-early protein 62 (IE62), and zoster is associated with neuropathic pain. Brain-derived neurotrophic factor (BDNF) is involved in the neuronal mechanism underlying pain hypersensitivity. Zoster is associated with prodrome and the robust production of booster antibody to VZV. We hypothesized that the intrathecal production of antibody to IE62 cross-reacting with BDNF and the nerve injury by skin lesions may augment allodynia in zoster by enhancing BDNF activity. Zoster produces a vesicular rash in a dermatomal distribution with sensory abnormalities, and it causes neurological complications such as zoster-associated pain (ZAP) or postherpetic neuralgia (PHN) (5,11,14,16,33). Zoster is associated with robust booster antibody production to varicella-zoster virus (VZV), which makes it possible to prevent or modify varicella as varicella-zoster immune globulin. PHN is the most frequent complication of zoster, occurring in 7 to 35% of patients, and it is characterized by the combination of constant pain, lancinating pain, and allodynia. However, the pathophysiology of ZAP and PHN has not been elucidated (10,17). VZV expresses the immediate-early protein 62 (IE62), a major transactivator of viral genes during lytic infection, and at least genes 4, 21, 29, 62, and 63 in latently infected ganglia (6,8,19,20,29,30). Although VZV or its products such as IE62 may be involved in the pathogenesis of PHN (12, 13), VZV is ubiquitously and latently distributed in sensory ganglia after varicella and zoster, but PHN is limited only to some patients with zoster.Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that plays an important role in the development and plasticity of the peripheral and central nervous systems (3, 37). BDNF is involved in the neuronal mechanism underlying clinical pain hypersensitivity, particularly neuropathic pain (7, 21-23, 27, 37, 38). BDNF from microglia has been reported to participate in the pain hypersensitivity that underlies tactile allodynia (7). We hypothesized that BDNF participates in the pathogenesis of PHN and examined the immune response to VZV and BDNF in sera from patients with zoster and PHN. We found immunological cross-reactivity between IE62 and BDNF, and this cross-reaction of IE62 and BDNF was characterized using anti-IE62 monoclonal antibody (anti-IE62 MAb) and anti-BDNF MAb. Surprisingly, the anti-IE62 MAb recognized both the linear epitope (amino acids 414 to 429, designated p414-429) of IE62 and the conformational epitope of BDNF, and it augmented the functional activity of BDNF in cultured neurons. Sera from patients with zoster and PHN recognized BDNF and augmented BDNF activity in cultured neurons. The augmentation of BDNF by anti-IE62 MAb reduced the threshold to mechanical allodynia in mice with
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