Neurochemistry international
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In most mature neurons, low levels of intracellular Cl- concentrations ([Cl-]i) are maintained by channels and transporters, particularly the K+-Cl- cotransporter 2 (KCC2), which is the only Cl- extruder in most neurons. Recent studies have implicated KCC2 expression in the molecular mechanisms underlying neuronal disorders, such as spasticity, epilepsy and neuropathic pain. Alterations in KCC2 expression have been associated with brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB). ⋯ Moreover, we focus on the role of KCC2 regulation via the BDNF-TrkB pathway in spinal cord injury and rehabilitation, as prior studies have shown that the BDNF-TrkB pathway can affect both the pathological development and functional amelioration of spinal cord injuries. Evidence suggests that rehabilitation using active exercise and mechanical stimulation can attenuate spasticity and neuropathic pain in animal models, likely due to the upregulation of KCC2 expression via the BDNF-TrkB pathway. Moreover, research suggests that such rehabilitation efforts may recover KCC2 expression without the use of exogenous BDNF.
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Review
Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases.
The number of bacterial cells living within the human body is approximately equal to, or greater than, the total number of human cells. This dynamic population of microorganisms, termed the human microbiota, resides mainly within the gastrointestinal tract. It is widely accepted that highly diverse and stable microbiota promote overall human health. ⋯ We provide an interpretation for the substantial evidence that healthy intestinal microbiota have the ability to positively regulate the neuroimmune responses in the CNS. Even though the evidence is mainly associative, it has been suggested that bacterial dysbiosis could contribute to an adverse neuroinflammatory state leading to increased risk of neurodegenerative diseases. Thus, developing strategies for regulating and maintaining healthy intestinal microbiota could be a valid approach for lowering individual risk and prevalence of neurodegenerative diseases.
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Review
Targeting mitochondrial dysfunction in CNS injury using Methylene Blue; still a magic bullet?
Complex, multi-factorial secondary injury cascades are initiated following traumatic brain injury, which makes this a difficult disease to treat. The secondary injury cascades following the primary mechanical tissue damage, are likely where effective therapeutic interventions may be targeted. One promising therapeutic target following brain injury are mitochondria. ⋯ Within this mixed mini review/research article there will be a general discussion of mitochondrial bioenergetics, followed by a brief discussion of traumatic brain injury and how mitochondria play an integral role in the neuropathological sequelae following an injury. We will also give an overview of one relatively new TBI therapeutic approach, Methylene Blue, currently being studied to ameliorate mitochondrial dysfunction following brain injury. We will also present novel experimental findings, that for the first time, characterize the ex vivo effect of Methylene Blue on mitochondrial function in synaptic and non-synaptic populations of mitochondria.
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Zellweger syndrome (ZS) is a neonatal-lethal genetic disease that affects all tissues, and features neuropathology that involves primary developmental defects as well as neurodegeneration. Neuropathological changes include abnormal neuronal migration affecting the cerebral hemispheres, cerebellum and inferior olivary complex, abnormal Purkinje cell arborisation, demyelination and post-developmental neuronal degeneration. ⋯ Attempts to explain the neuropathogenesis have implicated peroxisomal metabolic dysfunction, and more specifically the loss of peroxisomal products, such as plasmalogens and docosahexaenoic, and the accumulation of peroxisomal substrates, such as very-long-chain-fatty acids. In this review, consideration is also given to recent findings that implicate other candidate pathogenetic factors, such as mitochondrial dysfunction, oxidative stress, protein misfolding, aberrant cell signalling, and inflammation - factors that have also been identified as important in the pathogenesis of other neurological diseases.
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In acute neuronal insult events, such as stroke, traumatic brain injury, and spinal cord injury, pathological processes of secondary neuronal injury play a key role in the severity of insult and clinical prognosis. Along with nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is regarded as the third gasotransmitter and endogenous neuromodulator and plays multiple roles in the central nervous system under physiological and pathological states, especially in secondary neuronal injury. The endogenous level of H2S in the brain is significantly higher than that in peripheral tissues, and is mainly formed by cystathionine β-synthase (CBS) in astrocytes and released in response to neuronal excitation. ⋯ However, there are still some reports suggest that H2S elevates neuronal Ca(2+) concentration and may contribute to the formation of calcium overload in secondary neuronal injury. H2S also elicits calcium waves in primary cultures of astrocytes and may mediate signals between neurons and glia. Consequently, further exploration of the molecular mechanisms of H2S in secondary neuronal injury will provide important insights into its potential therapeutic uses for the treatment of acute neuronal insult events.