Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases.

Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca2+ flow through the membrane. Among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (KV), the largest family of K+ channels. Due to the ROS high levels in the aging brain, K+ channels might be affected by oxidative agents and be key in aging and neurodegeneration processes. This review provides new insight about channelopathies in the most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson's Disease, Huntington Disease or Spinocerebellar Ataxia. The main affected KV channels in these neurodegenerative diseases are the KV1, KV2.1, KV3, KV4 and KV7. Moreover, in order to prevent or repair the development of these neurodegenerative diseases, previous KV channel modulators have been proposed as therapeutic targets.

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer's Disease: Possible Therapeutic Role of KV1.3 Channel Blockade.

Increase of deposits of amyloid ß peptides in the extracellular matrix is landmark during Alzheimer's Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid ß deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid ß peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-α, IL-1ß) in response to reactive gliosis activated by the amyloid ß aggregates. Microglia activation correlated with an increase KV1.3 channels expression, protein levels and current density. Several studies highlight the importance of KV1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid ß accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that KV1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1ß and TNF-α through the NF-kB and p38MAPK pathway. Overall, we conclude that KV1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients.

In vitro P38MAPK inhibition in aged astrocytes decreases reactive astrocytes, inflammation and increases nutritive capacity after oxygen-glucose deprivation.

Proper astroglial functioning is essential for the development and survival of neurons and oligodendroglia under physiologic and pathological circumstances. Indeed, malfunctioning of astrocytes represents an important factor contributing to brain injury. However, the molecular pathways of this astroglial dysfunction are poorly defined. In this work we show that aging itself can drastically perturb astrocyte viability with an increase of inflammation, cell death and astrogliosis. Moreover, we demonstrate that oxygen glucose deprivation (OGD) has a higher impact on nutritive loss in aged astrocytes compared to young ones, whereas aged astrocytes have a higher activity of the anti-oxidant systems. P38MAPK signaling has been identified to be upregulated in neurons, astrocytes and microglia after ischemic stroke. By using a pharmacological p38α specific inhibitor (PH-797804), we show that p38MAPK pathway has an important role in aged astrocytes for inflammatory and oxidative stress responses with the subsequent cell death that occurs after OGD.

Glial Factors Regulating White Matter Development and Pathologies of the Cerebellum.

The cerebellum is a brain region that undergoes extremely dynamic growth during perinatal and postnatal development which is regulated by the proper interaction between glial cells and neurons with a complex concert of growth factors, chemokines, cytokines, neurotransmitters and transcriptions factors. The relevance of cerebellar functions for not only motor performance but also for cognition, emotion, memory and attention is increasingly being recognized and acknowledged. Since perturbed circuitry of cerebro-cerebellar trajectories can play a role in many central nervous system pathologies and thereby contribute to neurological symptoms in distinct neurodevelopmental and neurodegenerative diseases, is it the aim with this mini-review to highlight the pathways of glia-glia interplay being involved. The designs of future treatment strategies may hence be targeted to molecular pathways also playing a role in development and disease of the cerebellum.

Neuronal p38α mediates age-associated neural stem cell exhaustion and cognitive decline.

Neuronal activity regulates cognition and neural stem cell (NSC) function. The molecular pathways limiting neuronal activity during aging remain largely unknown. In this work, we show that p38MAPK activity increases in neurons with age. By using mice expressing p38α-lox and CamkII-Cre alleles (p38α∆-N), we demonstrate that genetic deletion of p38α in neurons suffices to reduce age-associated elevation of p38MAPK activity, neuronal loss and cognitive decline. Moreover, aged p38α∆-N mice present elevated numbers of NSCs in the hippocampus and the subventricular zone. These results reveal novel roles for neuronal p38MAPK in age-associated NSC exhaustion and cognitive decline.

Ischemic stroke in neonatal and adult astrocytes.

The objective of this paper is to review current information regarding astrocytes function after a stroke in neonatal and adult brain. Based on the current literature, there are some molecular differences related to blood brain barrier (BBB) homeostasis disruption, inflammation and reactive oxygen species (ROS) mediated injury between the immature and mature brain after an ischemic event. In particular, astrocytes, the main glial cells in brain, play a different role in neonatal and adult brain after stroke, as time course of glial activation is strongly age dependent. Moreover, the present review provides further insight into the therapeutic approaches of using neonatal and adult astrocytes after stroke. More research will be needed in order to translate them into an effective treatment against stroke, the second main cause of death and disability worldwide.

SOX2 expression diminishes with ageing in several tissues in mice and humans.

SOX2 (Sex-determining region Y box 2) is a transcription factor expressed in several foetal and adult tissues and its deregulated activity has been linked to chronic diseases associated with ageing. Nevertheless, the level of SOX2 expression in aged individuals at the tissue level has not previously been examined. In this work, we show that SOX2 expression decreases significantly in the brain with ageing, in both humans and rodents. The administration of resveratrol for 6 months in mice partly attenuated this reduction. We also identified an age-related decline in SOX2 mRNA and protein expression in several other organs, namely, the lung, heart, kidney, spleen and liver. Moreover, peripheral blood mononuclear cells (PBMCs) from elderly expressed lower levels of SOX2 than those from young individuals. Mechanistically, SOX2 expression inversely correlates with p16Ink4a levels. Together, these data show a widespread decrease in SOX2 with age, suggesting that the decline in SOX2 expression might be used as a biomarker of ageing.

Autophagy in stem cell aging.

Aging is responsible for changes in mammalian tissues that result in an imbalance to tissue homeostasis and a decline in the regeneration capacity of organs due to stem cell exhaustion. Autophagy is a constitutive pathway necessary to degrade damaged organelles and protein aggregates. Autophagy is one of the hallmarks of aging, which involves a decline in the number and functionality of stem cells. Recent studies show that stem cells require autophagy to get rid of cellular waste produced during the quiescent stage. In particular, two independent studies in muscle and hematopoietic stem cells demonstrate the relevance of the autophagy impairment for stem cell exhaustion and aging. In this review, we summarize the main results of these works, which helped to elucidate the impact of autophagy in stem cell activity as well as in age-associated diseases.

Recent advances in cochlear hair cell regeneration-A promising opportunity for the treatment of age-related hearing loss.

The objective of this paper is to review current information regarding the treatment of age-related hearing loss by using cochlear hair cell regeneration. Recent advances in the regeneration of the inner ear, including the usefulness of stem cells, are also presented. Based on the current literature, cochlear cell regeneration may well be possible in the short term and cochlear gene therapy may also be useful for the treatment of hearing loss associated with ageing. The present review provide further insight into the pathogenesis of Inner Ear senescence and aged-related hearing loss and facilitate the development of therapeutic strategies to repair hair cells damaged by ageing. More research will be needed in order to translate them into an effective treatment for deafness linked to cochlear senescence in humans.

Role of Antioxidants in Neonatal Hypoxic-Ischemic Brain Injury: New Therapeutic Approaches.

Hypoxic-ischemic brain damage is an alarming health and economic problem in spite of the advances in neonatal care. It can cause mortality or detrimental neurological disorders such as cerebral palsy, motor impairment and cognitive deficits in neonates. When hypoxia-ischemia occurs, a multi-faceted cascade of events starts out, which can eventually cause cell death. Lower levels of oxygen due to reduced blood supply increase the production of reactive oxygen species, which leads to oxidative stress, a higher concentration of free cytosolic calcium and impaired mitochondrial function, triggering the activation of apoptotic pathways, DNA fragmentation and cell death. The high incidence of this type of lesion in newborns can be partly attributed to the fact that the developing brain is particularly vulnerable to oxidative stress. Since antioxidants can safely interact with free radicals and terminate that chain reaction before vital molecules are damaged, exogenous antioxidant therapy may have the potential to diminish cellular damage caused by hypoxia-ischemia. In this review, we focus on the neuroprotective effects of antioxidant treatments against perinatal hypoxic-ischemic brain injury, in the light of the most recent advances.

Antioxidant Treatments Recover the Alteration of Auditory-Evoked Potentials and Reduce Morphological Damage in the Inferior Colliculus after Perinatal Asphyxia in Rat.

Maturation of the auditory pathway is dependent on the central nervous system myelination and it can be affected by pathologies such as neonatal hypoxic ischemic (HI) encephalopathy. Our aim was to evaluate the functional integrity of the auditory pathway and to visualize, by histological and cellular methods, the damage to the brainstem using a neonatal rat model of HI brain injury. To carry out this morphofunctional evaluation, we studied the effects of the administration of the antioxidants nicotine, melatonin, resveratrol and docosahexaenoic acid after hypoxia-ischemia on the inferior colliculus and the auditory pathway. We found that the integrity of the auditory pathway in the brainstem was altered as a consequence of the HI insult. Thus, the auditory brainstem response (ABR) showed increased I-V and III-V wave latencies. At a histological level, HI altered the morphology of the inferior colliculus neurons, astrocytes and oligodendricytes, and at a molecular level, the mitochondria membrane potential and integrity was altered during the first hours after the HI and reactive oxygen species (ROS) activity is increased 12 h after the injury in the brainstem. Following antioxidant treatment, ABR interpeak latency intervals were restored and the body and brain weight was recovered as well as the morphology of the inferior colliculus that was similar to the control group. Our results support the hypothesis that antioxidant treatments have a protective effect on the functional changes of the auditory pathway and on the morphological damage which occurs after HI insult.

Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats.

Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia.

Effect of neonatal asphyxia on the impairment of the auditory pathway by recording auditory brainstem responses in newborn piglets: a new experimentation model to study the perinatal hypoxic-ischemic damage on the auditory system.

INTRODUCTION: Hypoxia-ischemia (HI) is a major perinatal problem that results in severe damage to the brain impairing the normal development of the auditory system. The purpose of the present study is to study the effect of perinatal asphyxia on the auditory pathway by recording auditory brain responses in a novel animal experimentation model in newborn piglets. METHOD: Hypoxia-ischemia was induced to 1.3 day-old piglets by clamping 30 minutes both carotid arteries by vascular occluders and lowering the fraction of inspired oxygen. We compared the Auditory Brain Responses (ABRs) of newborn piglets exposed to acute hypoxia/ischemia (n = 6) and a control group with no such exposure (n = 10). ABRs were recorded for both ears before the start of the experiment (baseline), after 30 minutes of HI injury, and every 30 minutes during 6 h after the HI injury. RESULTS: Auditory brain responses were altered during the hypoxic-ischemic insult but recovered 30-60 minutes later. Hypoxia/ischemia seemed to induce auditory functional damage by increasing I-V latencies and decreasing wave I, III and V amplitudes, although differences were not significant. CONCLUSION: The described experimental model of hypoxia-ischemia in newborn piglets may be useful for studying the effect of perinatal asphyxia on the impairment of the auditory pathway.

Cerebral state index during propofol anesthesia: a comparison with the bispectral index and the A-line ARX index.

BACKGROUND: The objective of this study was to prospectively test the Cerebral State Index designed for measuring the depth of anesthesia. The Cerebral State Index is calculated using a fuzzy logic combination of four subparameters of the electroencephalographic signal. The performance of the Cerebral State Index was compared with that of the Bispectral Index and the A-Line ARX Index. METHODS: This study applied raw data from two previously published clinical protocols. The patients in protocol 1 were given a continuous propofol infusion, 300 ml/h, until 80% of burst suppression occurred. In protocol 2, a stepwise increased target-controlled infusion of propofol was administered to patients until loss of response to noxious stimuli while the Observer's Assessment of Alertness and Sedation was registered every 4 min. The Cerebral State Index was calculated off-line from the recorded electroencephalographic data. The Spearman rank correlation coefficient between electronic indices and the effect site concentration of propofol was calculated along with the prediction probability of each index to predict the Observer's Assessment of Alertness and Sedation level. RESULTS: The Spearman rank correlation coefficients between the Cerebral State Index, Bispectral Index, and A-Line ARX Index and the propofol effect site concentration were -0.94, -0.89, and -0.82, respectively, in protocol 1, whereas the prediction probability values between the Cerebral State Index, Bispectral Index, and A-Line ARX Index and the Observer's Assessment of Alertness and Sedation score in protocol 2 were 0.92, 0.93, and 0.91, respectively. CONCLUSION: The Cerebral State Index detects well the graduated levels of propofol anesthesia when compared with the propofol effect site concentration and the Observer's Assessment of Alertness and Sedation score.