Increase in serum homocysteine is shown to be a potential risk factor for cognitive impairment. Evidence suggests that vitamin B supplementation may reduce cognitive decline by lowering the homocysteine levels. The current meta-analysis evaluated the efficacy of folic acid along with vitamin B12 and/or B6 in lowering homocysteine, thereby attenuating cognitive decline in elderly patients with Alzheimer disease or dementia. Randomized controlled trials (RCTs) comparing the efficacy of folate and B vitamin supplementation in patients with cognitive decline secondary to Alzheimer disease or dementia were identified using the keywords, "homocysteine, hyper-homocysteinemia, B vitamin, vitamin B6, B12, folic acid, cognitive, Alzheimer's disease, and dementia." The outcome measures analyzed were the Mini-Mental State Examination (MMSE) score and serum homocysteine. Of the 77 studies identified, 4 RCTs were included in the current meta-analysis. The baseline characteristics, age, and gender distribution of patients among the 2 groups (supplement vs placebo) were comparable. The results reveal that the intervention group achieved significantly greater reduction in homocysteine levels than the control (pooled difference in means = -3.625, 95% confidence interval [CI] = -5.642 to -1.608, P < .001). However, no significant difference in MMSE (pooled difference in means = 0.027, 95% CI = -0.518 to 0.573, P = 0.921) was observed between the groups. Taken together, vitamin B supplementation was effective in reducing serum homocysteine levels. However, it did not translate into cognitive improvement, indicating that the existing data on vitamin B-induced improvement in cognition by lowering homocysteine levels are conflicting.
The neuroprotective agents currently used to treat Alzheimer's disease (AD) often only target one aspect of the disease process. Therefore, identifying effective drug targets associated with the pathogenesis of AD is critical for the production of novel AD therapeutic strategies. The present study aimed to investigate the underlying mechanisms of the neuroprotective effects of Rg1 on a rat model of AD. A double transgenic β‑amyloid (Aβ) precursor protein/PS1 rat model was established, which co‑expressed mutations associated with AD. Aβ plaques and neurofibrillary tangles (NFTs) were detected by immunohistochemistry. The detection of the protein expression levels of caspase‑3 and terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling (TUNEL) staining were used to determine the level of apoptosis in the brain tissue. The expression levels of the endoplasmic reticulum (ER) stress biomarker, glucose‑regulated protein 78 (Grp78), and the mitochondrial apoptosis biomarkers, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax), were analyzed by western blotting. Furthermore, the expression of the proteins associated with the ER stress unfolded protein response (UPR) was determined, in order to examine the levels of ER stress. The mRNA expression of downstream genes of UPR were also detected by reverse transcription‑polymerase chain reaction. The protein expression levels of the apoptosis‑associated phosphorylated‑c‑Jun N‑terminal protein kinase (p‑JNK), caspase‑12 and cAMP response element‑binding transcription factor homologous protein were determined by western blotting. The results of the present study indicated that the accumulation of NFTs and Aβ plaques was significantly decreased in the Rg1‑treated AD rats, compared with untreated AD rats. The expression of caspase‑3 and the number of TUNEL‑positive cells were also significantly decreased in the Rg1‑treated rats, as compared with the AD rats. Furthermore, treatment with Rg1 significantly reduced the expression of Grp78, and triggered inositol‑requiring enzyme‑1 (IRE‑1) and phosphorylated protein kinase RNA‑like ER kinase‑associated ER stress. The IRE‑1 UPR pathway downstream gene, tumor necrosis factor receptor‑associated factor 2, was significantly decreased in rats treated with Rg1, compared with untreated AD rats. Furthermore, the activation of p‑JNK was also inhibited when AD rats were treated with Rg1. In conclusion, Rg1 was shown to function as an important factor that inhibits the accumulation of NFTs and Aβ via inhibition of the ER stress‑mediated pathway. Blocking of this pathway was triggered by the IRE‑1 and TRAF2 pathway, as a result of inhibition of the expression of p‑JNK.
Although triptans are widely used for treating acute migraine, they are contraindicated or not effective in a large proportion of patients. Hence, alternative treatments are needed. Calcitonin gene-related peptide receptor antagonists, such as telcagepant, have been under investigation as a treatment for acute migraine. A meta-analysis of the efficacy of telcagepant vs. placebo and triptans (zolmitriptan or rizatriptan) was performed. Randomized controlled trials were indentified from databases using the following search terms: migraine; calcitonin gene-related peptide; calcitonin gene-related peptide receptor antagonists; efficacy; safety, and telcagepant. The primary outcome measure was pain freedom 2 hours after first treatment. The secondary outcome measure was pain relief 2 hours after first treatment. Eight trials were included in the meta-analysis (telcagepant = 4011 participants). The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.70, 95% confidence interval = 2.27-3.21, P < 0.001) and triptans over telcagepant (odds ratio = 0.68, 95% confidence interval = 0.56-0.83, P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.48, 95% confidence interval = 2.18-2.81, P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (odds ratio = 0.76, 95% confidence interval = 0.57-1.01, P = 0.061). These findings indicate that telcagepant can be effective for treating acute migraine. Calcitonin gene-related peptide receptor antagonists represent a potentially important alternative means of treating acute migraine.
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