Therapeutic Effects of Combination of Nebivolol and Donepezil: Targeting Multifactorial Mechanisms in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1G93A mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.

Photobiomodulation (660 nm) therapy reduces oxidative stress and induces BDNF expression in the hippocampus.

Photobiomodulation therapy (PBMT) effects an important role in neural regeneration and function enhancement, such as expression of nerve growth factor and nerve regeneration, in neuronal tissues, and inhibition of cell death by amyloid beta in neurons is inhibited by PBMT. However, there no studies evaluated the effects of PBMT on oxidative stress in the hippocampus. The aim of this study is to evaluate the effects of PBMT on oxidative stress in the hippocampus. This study assessed the anti-oxidative effect, the expression of BDNF and antioxidant enzymes, as well as the activation of cAMP response element binding (CREB) and extracellular signal-regulated kinase (ERK) signal transduction pathways assess using a hippocampal cell line (HT-22) and mouse organotypic hippocampal tissues by PBMT (LED, 660 nm, 20 mW/cm2). PBMT inhibited HT-22 cell death by oxidative stress and increased BDNF expression via ERK and CREB signaling pathway activation. In addition, PBMT increased BDNF expression in hippocampal organotypic slices and the levels of phosphorylated ERK and CREB, which were reduced by oxidative stress, as well as the expression of the antioxidant enzyme superoxide dismutase. These data demonstrate that PBMT inhibits hippocampal damage induced by oxidative stress and increases the expression of BDNF, which can be used as an alternative to treat a variety of related disorders that lead to nerve damage. Activation and redox homeostasis in neuronal cells may be a notable mechanism of the 660-nm PBMT-mediated photobioreactivity.

Early Detection of Aß Deposition in the 5xFAD Mouse by Amyloid PET.

Purpose.18F-FC119S is a positron emission tomography (PET) tracer for imaging ß-amyloid (Aß) plaques in Alzheimer's disease (AD). The aim of this study is to evaluate the efficacy of 18F-FC119S in quantitating Aß deposition in a mouse model of early amyloid deposition (5xFAD) by PET. Method. Dynamic 18F-FC119S PET images were obtained in 5xFAD (n = 5) and wild-type (WT) mice (n = 7). The brain PET images were spatially normalized to the M. Mirrione T2-weighted mouse brain MR template, and the volumes of interest were then automatically drawn on the cortex, hippocampus, thalamus, and cerebellum. The specific binding of 18F-FC119S to Aß was quantified as the distribution volume ratio using Logan graphical analysis with the cerebellum as a reference tissue. The Aß levels in the brain were also confirmed by immunohistochemical analysis. Result. For the 5xFAD group, radioactivity levels in the cortex, the hippocampus, and the thalamus were higher than those for the WT group. In these regions, specific binding was approximately 1.2-fold higher in 5xFAD mice than in WT. Immunohistochemistry supported these findings; the 5xFAD showed severe Aß deposition in the cortex and hippocampus in contrast to the WT group. Conclusion. These results demonstrated that 18F-FC119S PET can successfully distinguish Aß depositions in 5xFAD mice from WT.

The Natural Substance MS-10 Improves and Prevents Menopausal Symptoms, Including Colpoxerosis, in Clinical Research.

Many natural substances were screened to develop nutraceuticals that reduce menopausal symptoms. A complex of Cirsium japonicum var. maackii and Thymus vulgaris extracts, named MS-10, had significant positive effects. Under a low concentration of estrogen, which represents postmenopausal physiological conditions, MS-10 had beneficial effects on estrogen receptor-expressing MCF-7 cells by reversibly enhancing estrogen activity. In addition, in the ovariectomized rat model, changes in bone-specific alkaline phosphatase activity and osteocalcin, as well as low-density lipoprotein cholesterol and triglyceride levels were significantly decreased by MS-10. These results show that MS-10 protected bone health and reduced metabolic disturbances. Furthermore, in a clinical study, all menopausal symptoms, including hot flushes, parenthesis, insomnia, nervousness, melancholia, vertigo, fatigue, rheumatic pain, palpitations, formication, and headache, as well as colpoxerosis, were significantly improved by taking MS-10 for 90 days. Therefore, the evidence supports that MS-10 is an effective natural substance that can safely improve menopausal symptoms, including colpoxerosis.

Recent advances in radiopharmaceutical application of matched-pair radiometals.

Theranostic medicine is relatively a new term that describes integration of diagnostic and therapeutic functions within the same platform of pharmaceuticals. Such a design may in principle permit the molecular diagnosis, targeted therapy, and simultaneous monitoring and treatment necessary to achieve personalized medicine for cancer. Theranostic radiopharmaceuticals, for instance, carry the properties of both diagnostic radioimaging and radioimmunotherapy (RIT). As nuclear imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) have excellent sensitivity and can provide biochemical information on pathological conditions, much effort has been made in order to accomplish a more effective and powerful theranostic combination. Some recent examples include SPECT-therapy, PET-therapy, and therapy-therapy. In particular, the combined therapy-therapy method is the result of realization that RIT relying on a single radioisotope has an inherent limitation for practical cancer treatment. Thus the success of theranostic nuclear medicine depends on a proper choice of different radioisotopes that will lead to a perfect couple. This pair of radioisotopes is called matched-pair radioisotopes. The structural motif for radiopharmaceuticals based on matched-pair consists of a bifunctional chelator (BFCA) and a biologically active molecule (BAM). This review will focus on recent advances in radiopharmaceutical application of matched-pair radiometals in clinics as well as preclinics.

Prevalence and factors affecting glucosamine use in Korea: a survey-based study.

Glucosamine and chondroitin are widely used as pharmaceutical and dietary supplements. However, there is a lack of information regarding consumer consumption of glucosamine and chondroitin in the Republic of Korea. We investigated the prevalence and factors affecting the use of glucosamine products in the general population aged 40 years and older in the Republic of Korea. We conducted this descriptive and exploratory study using a telephone-based survey with a structured questionnaire. We randomly selected subjects using a proportional allocation method based on age, gender, and region. We started the survey on September 19, 2009, and continued the survey until we obtained 1,000 respondents who were currently taking glucosamine or chondroitin, which occured on September 30, 2009. Among the 8,135 people approached, the response rate was 29.6%. A total of 12.2% of respondents (n = 991) were current users of glucosamine, while only 0.1% (n = 9) were current users of chondroitin. Two-fifths of current glucosamine users were not diagnosed with osteoarthritis by a doctor nor did they experience arthritis pain. These participants used glucosamine to maintain and promote joint health. Information on glucosamine was mainly obtained through advertisements on television or the Internet. Seventy percent of current users indicated that they did not know the composition of the glucosamine they took. Appropriate information and guides concerning glucosamine or chondroitin usage should be provided by expert clinicians because of the accessibility of both these cartilage derivatives as supplements and medical drugs in the Republic of Korea.