Front Cell Neurosci
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Front Cell Neurosci · Jan 2014
ReviewGap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases.
Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. ⋯ Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.
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Front Cell Neurosci · Jan 2014
ReviewBenefits of exercise intervention in reducing neuropathic pain.
Peripheral neuropathy is a widespread and potentially incapacitating pathological condition that encompasses more than 100 different forms and manifestations of nerve damage. The diverse pathogenesis of peripheral neuropathy affects autonomic, motor and/or sensory neurons, and the symptoms that typify the condition are abnormal cutaneous sensation, muscle dysfunction and, most notably, chronic pain. Chronic neuropathic pain is difficult to treat and is often characterized by either exaggerated responses to painful stimuli (hyperalgesia) or pain resulting from stimuli that would not normally provoke pain (allodynia). ⋯ The development of neuropathic pain is a highly complex and multifactorial process, but recent evidence indicates that the activation of spinal glial cells via the enzyme glycogen synthase kinase 3 and increases in the production of both pro-inflammatory cytokines and brain derived neurotropic factor are crucial steps. Since many of the most common causes of peripheral neuropathy cannot be fully treated, it is critical to understand that routine exercise may not only help prevent some of those causes, but that it has also proven to be an effective means of alleviating some of the condition's most distressing symptoms. More research is required to elucidate the typical mechanisms of injury associated with peripheral neuropathy and the exercise-induced benefits to those mechanisms.
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Front Cell Neurosci · Jan 2014
ReviewNeuronal migration and its disorders affecting the CA3 region.
In this review, we focus on CA3 neuronal migration disorders in the rodent. We begin by introducing the main steps of hippocampal development, and we summarize characteristic hippocampal malformations in human. ⋯ We successively describe their molecular, physiological and behavioral phenotypes that together contribute to a better understanding of CA3-dependent functions. We finally discuss potential factors underlying the CA3 vulnerability revealed by these mouse mutants and that may also contribute to other human neurological and psychiatric disorders.
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Front Cell Neurosci · Jan 2014
ReviewCurrent view on the functional regulation of the neuronal K(+)-Cl(-) cotransporter KCC2.
In the mammalian central nervous system (CNS), the inhibitory strength of chloride (Cl(-))-permeable GABAA and glycine receptors (GABAAR and GlyR) depends on the intracellular Cl(-) concentration ([Cl(-)]i). Lowering [Cl(-)]i enhances inhibition, whereas raising [Cl(-)]i facilitates neuronal activity. A neuron's basal level of [Cl(-)]i, as well as its Cl(-) extrusion capacity, is critically dependent on the activity of the electroneutral K(+)-Cl(-) cotransporter KCC2, a member of the SLC12 cation-Cl(-) cotransporter (CCC) family. ⋯ Accordingly, identifying the key upstream molecular mediators governing the functional regulation of KCC2, and modifying these signaling pathways with small molecules, might constitute a novel neurotherapeutic strategy for multiple diseases. Here, we discuss recent advances in the understanding of the mechanisms regulating KCC2 activity, and of the role these mechanisms play in neuronal Cl(-) homeostasis and GABAergic neurotransmission. As KCC2 mediates electroneutral transport, the experimental recording of its activity constitutes an important research challenge; we therefore also, provide an overview of the different methodological approaches utilized to monitor function of KCC2 in both physiological and pathological conditions.
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Chronic pain represents a major problem in clinical medicine. Whilst the acute pain that is associated with tissue injury is a protective signal that serves to maintain homeostasis, chronic pain is a debilitating condition that persists long after the inciting stimulus subsides. Chronic neuropathic pain that develops following damage or disease of the nervous system is partially treated by current therapies, leaving scope for new therapies to improve treatment outcome. ⋯ Thus, identification of mechanisms regulating neuro-immune interactions that occur during neuropathic pain may provide future therapeutic targets. Specifically, chemokines and their receptors play a pivotal role in mediating neuro-immune communication which leads to increased nociception. In particular, the chemokine Fractalkine (FKN) and the CX3CR1 receptor have come to light as a key signaling pair during neuropathic pain states.