Increased oxidative stress, inflammation, and glutamate: Potential preventive and therapeutic targets for hearing disorders.

Hearing disorders constitute one of the major health concerns in the USA. Decades of basic and clinical studies have identified numerous ototoxic agents and investigated their modes of action on the inner ear, utilizing tissue culture as well as animal and human models. Current preventive and therapeutic approaches are considered unsatisfactory. Therefore, additional modalities should be developed. Many studies suggest that increased levels of oxidative stress, chronic inflammation, and glutamate play an important role in the initiation and progression of damage to the inner ear leading to hearing impairments. To prevent these cellular deficits, antioxidants, anti-inflammatory agents, and antagonists of glutamate receptor have been used individually or in combination with limited success. It is essential, therefore, to simultaneously enhance the levels of antioxidant enzymes by activating the Nrf2 (a nuclear transcriptional factor) pathway, dietary and endogenous antioxidant compounds, and B12-vitamins in order to reduce the levels of oxidative stress, chronic inflammation, and glutamate at the same time. This review presents evidence to show that increased levels of these cellular metabolites, biochemical or factors are involved in the pathogenesis of cochlea leading to hearing impairments. It presents scientific rationale for the use of a mixture of micronutrients that may decrease the levels of oxidative damage, chronic inflammation, and glutamate at the same time. The benefits for using oral administration of proposed micronutrient mixture in humans are presented. Animal and limited human studies indirectly suggest that orally administered micronutrients can accumulate in the inner ear. Therefore, this route of administration may be useful in prevention, and in combination with standard care, in improved management of hearing problems following exposure to well-recognized and studied ototoxic agents, such as noise, cisplatin, aminoglycoside antibiotics, and advanced age

Distinctive cellular response to aluminum based adjuvants.

Aluminum-based adjuvants (ABAs) are used in human vaccines to enhance the magnitude of protective immune responses elicited against specific pathogens. One hypothesis is that stress signals released by aluminum-exposed necrotic cells play a role in modulating an immune response that contributes to the adjuvant's effectiveness. We hypothesized that aluminum adjuvant-induced necrosis would be similar irrespective of cellular origin or composition of the adjuvant. To test this hypothesis, human macrophages derived from peripheral monocytic cell line (THP-1) and cells derived from the human brain (primary astrocytes) were evaluated. Three commercially available formulations of ABAs (Alhydrogel, Imject alum, and Adju-Phos) were examined. Alum was also used as a reference. Cell viability, reactive oxygen species formation, and production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were quantified. Cells were exposed to different concentrations (10-100 μg/mL) of the adjuvants for 24 h or 72 h. The two FDA approved adjuvants (Alhydrogel and Adju-Phos) decreased cell viability in both cell types. At the 72 h time point, the decrease in viability was accompanied with increased ROS formation. The size of the aluminum agglomerates was not relatable to the changes observed. After exposure to ABAs, astrocytes and macrophages presented a distinct profile of cytokine secretion which may relate to the function and unique characteristics of each cell type. These variations indicate that aluminum adjuvants may have differing capability of activating cells of different origin and thus their utility in specific vaccine design should be carefully assessed for optimum efficacy

Aspects of the immune system that impact brain function.

The conditions required for effective immune responses to viral or bacterial organisms and chemicals of exogenous origin and to intrinsic molecules of abnormal configuration, are briefly outlined. This is followed by a discussion of endocrine and environmental factors that can lead to excessive continuation of immune activity and persistent elevation of inflammatory responses. Such disproportionate activity becomes increasingly pronounced with aging and some possible reasons for this are considered. The specific vulnerability of the nervous system to prolonged immune events is involved in several disorders frequently found in the aging brain. In addition of being a target for inflammation associated with neurodegenerative disease, the nervous system is also seriously impacted by systemically widespread immune disturbances since there are several means by which immune information can access the CNS. The activation of glial cells and cells of non-nervous origin that form the basis of immune responses within the brain, can occur in differing modes resulting in widely differing consequences. The events underlying the relatively frequent occurrence of derangement and hyperreactivity of the immune system are considered, and a few potential ways of addressing this common condition are described

Nanoparticles and Colloids as Contributing Factors in Neurodegenerative Disease

This review explores the processes underlying the deleterious effects of the presence of insoluble or colloidal depositions within the central nervous system. These materials are chemically unreactive and can have a prolonged residence in the brain. They can be composed of mineral or proteinaceous materials of intrinsic or exogenous origin. Such nanoparticulates and colloids are associated with a range of slow-progressing neurodegenerative states. The potential common basis of toxicity of these materials is discussed. A shared feature of these disorders involves the appearance of deleterious inflammatory changes in the CNS. This may be due to extended and ineffective immune responses. Another aspect is the presence of excess levels of reactive oxygen species within the brain. In addition with their induction by inflammatory events, these may be further heightened by the presence of redox active transition metals to the large surface area afforded by nanoparticles and amphipathic micelles

Anthropogenic pollutants may increase the incidence of neurodegenerative disease in an aging population.

The current world population contains an ever-increasing increased proportion of the elderly. This is due to global improvements in medical care and access to such care. Thus, a growing incidence of age-related neurodegenerative disorders is to be expected. Increased longevity also allows more time for interaction with adverse environmental factors that have the potential exert a gradual pressure, facilitating the onset of organismic aging. Nearly all neurodegenerative disorders have a relatively minor genetic element and a larger idiopathic component. It is likely that some of the unknown factors promoting neurological disease involve the appearance of some deleterious aspects of senescence, elicited prematurely by low but pervasive levels of toxic materials present in the environment. This review considers the nature of such possible toxicants and how they may hasten neurosenescence. An enhanced rate of emergence of normal age-related changes in the brain can lead to increased incidence of those specific neurological disorders where aging is an essential requirement. In addition, some xenobiotic agents appear to have the capability of engendering specific neurodegenerative disorders and some of these are also considered

Impact of Gene-Gender Effects of Adrenergic Polymorphisms on Hypothalamic-Pituitary-Adrenal Axis Activity in Depressed Patients

Objective: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. Methods: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of alpha 2-adrenoceptor (ADRA2A -1291C -> G) and the beta 2-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. Results: Male ADRA2A -1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. Conclusions: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders. Copyright (c) 2008 S. Karger AG, Base

Melatonin Alters Age-Related Changes in Transcription Factors and Kinase Activation

Male mice were fed 40 ppm melatonin for 2 months prior to sacrifice at age 26 months, and compared with both 26 and 4 month-old untreated controls. The nuclear translocation of NF-κB increased with age in both brain and spleen and this was reversed by melatonin only in brain. Another transcription factor, AP-1 was increased with age in the spleen and not in brain and this could be blocked by melatonin treatment. The fraction of the active relative to the inactive form of several enabling kinases was compared. The proportion of activated ERK was elevated with age in brain and spleen but this change was unresponsive to melatonin. A similar age-related increase in glial fibrillary acidic protein (GFAP) was also refractory to melatonin treatment. The cerebral melatonin M1 receptor decreased with age in brain but increased in spleen. The potentially beneficial nature of melatonin for the preservation of brain function with aging was suggested by the finding that an age-related decline in cortical synaptophysin levels was prevented by dietary melatonin

Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?

Prion diseases are a group of incurable infectious terminal neurodegenerative diseases caused by the aggregated misfolded PrPsc in selected mammals including humans. The complex physical interaction between normal prion protein PrPc and infectious PrPsc causes conformational change from the α- helix structure of PrPc to the β-sheet structure of PrPsc, and this process is repeated. Increased oxidative stress is one of the factors that facilitate the conversion of PrPc to PrPsc. This overview presents evidence to show that increased oxidative stress and inflammation are involved in the progression of this disease. Evidence is given for the participation of redoxsensitive metals Cu and Fe with PrPsc inducing oxidative stress by disturbing the homeostasis of these metals. The fact that some antioxidants block the toxicity of misfolded PrPc peptide supports the role of oxidative stress in prion disease. After exogenous infection in mice, PrPsc enters the follicular dendritic cells where PrPsc replicates before neuroinvasion where they continue to replicate and cause inflammation leading to neurodegeneration. Therefore, reducing levels of oxidative stress and inflammation may decrease the rate of the progression of this disease. It may be an important order to reduce oxidative stress and inflammation at the same time. This may be achieved by increasing the levels of antioxidant enzymes by activating the Nrf2 pathway together with simultaneous administration of dietary and endogenous antioxidants. It is proposed that a mixture of micronutrients could enable these concurrent events thereby reducing the progression of human prion disease