Neuroscience
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Mitochondrial dysfunctions have been described in Down syndrome (DS) caused by either partial or full trisomy of chromosome 21 (HSA21). Mitochondria play a crucial role in various vital functions in eukaryotic cells, especially in energy production, calcium homeostasis and programmed cell death. The function of mitochondria is primarily regulated by genes encoded in the mitochondrion and nucleus. ⋯ This includes impaired mitochondrial dynamics, structural defects and dysregulated bioenergetic profiles such as OXPHOS deficiency and reduced ATP production. Various therapeutic approaches for modulating energy deficits in DS, effects and molecular mechanism of gene therapy and drugs that exert protective effects through modulation of mitochondrial function and attenuation of oxidative stress in DS cells were discussed. It is prudent that improving DS pathophysiological conditions or quality of life may be feasible by targeting something as simple as cellular mitochondrial biogenesis and function.
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Alzheimer's disease (AD) is a disorder of the central nervous system that is typically marked by progressive cognitive impairment and memory loss. Amyloid β plaque deposition and neurofibrillary tangles with hyperphosphorylated tau are the two hallmark pathologies of AD. In mammalian cells, autophagy clears aberrant protein aggregates, thus maintaining proteostasis as well as neuronal health. ⋯ On the other hand, defective autophagy has been found to induce the production of the neuroprotective factor fibroblast growth factor 21 (FGF21), although the underlying mechanism is unclear. In this review, we highlight the significance of aberrant autophagy in the pathogenesis of AD, discuss the possible mechanisms by which defective autophagy induces FGF21 production, and analyze the potential of FGF21 in the treatment of AD. The findings provide some insights into the potential role of FGF21 and autophagy in the pathogenesis of AD.
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Pregnancy is associated with profound acute and long-term physiological changes, but the effects of such changes on brain injury outcomes are unclear. Here, we examined the effects of previous pregnancy and maternal experience (parity) on acute neuroinflammatory responses to lateral fluid percussion injury (FPI), a well-defined experimental traumatic brain injury (TBI) paradigm. Multiparous (2-3 pregnancies and motherhood experiences) and age-matched nulliparous (no previous pregnancy or motherhood experience) female mice received either FPI or sham injury and were euthanized 3 days post-injury (DPI). ⋯ However, multiparous females had fewer CD45+ cells near the site of injury compared to nulliparous females, which was associated with preserved aquaporin-4 polarization, suggesting that parity may influence leukocyte recruitment to the site of injury and maintenance of blood brain barrier permeability following TBI. Additionally, relative cortical Il6 gene expression following TBI was dependent on parity such that TBI increased Il6 expression in nulliparous, but not multiparous, mice. Together, this work suggests that reproductive history may influence acute neuroinflammatory outcomes following TBI in females.
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Cannabinoids regulate analgesia, which has aroused much interest in identifying new pharmacological therapies in the management of refractory pain. Voltage-gated Na+ channels (Navs) play an important role in inflammatory and neuropathic pain. In particular, Nav1.9 is involved in nociception and the understanding of its pharmacology has lagged behind because it is difficult to express in heterologous systems. ⋯ In agreement with the experimental evidence, our computer simulations revealed that ACEA binds Tyr1599 of the local anaesthetics binding site of the hNav1.9, contacting residues that bind cannabinol (CBD) in the NavMs channel. ACEA adopted a conformation remarkably similar to the crystallographic conformation of anandamide on a non-homologous protein, obstructing the Na+ permeation pathway below the selectivity filter to occupy a highly conserved binding pocket at the intracellular side. These results describe a mechanism of action, possibly involved in cannabinoid analgesia.
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Perineuronal nets (PNNs) are structures that contain extracellular matrix chondroitin sulfate proteoglycan and surround the soma and dendrites of various neuronal cell types. They are involved in synaptic plasticity and undertake important physiological functions. Altered expression of PNNs has been demonstrated in the brains of autism-related animal models. ⋯ First, we performed wisteria floribunda agglutinin staining of the whole brain of Shank3B-/- mice, and found wisteria floribunda agglutinin-positive PNNs are significantly increased in the cerebellar interpositus nucleus (IntP) in Shank3B-/- mice compared to control littermates. After degradation of PNNs in the IntP by chondroitinase ABC, the repetitive behaviors of Shank3B-/- mice were decreased, while their social behaviors were ameliorated. These results suggested that PNNs homeostasis is involved in the regulation of social behavior, revealing a potential therapeutic strategy targeting PNNs in the IntP for the treatment of autism spectrum disorder.