Frontiers in neuroscience
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Frontiers in neuroscience · Jan 2020
ReviewGABAergic Inhibitory Interneuron Deficits in Alzheimer's Disease: Implications for Treatment.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically by amyloid plaques, neuronal loss, and neurofibrillary tangles. Abnormal amyloid β-protein (Aβ) deposition in the brain is often thought of as a major initiating factor in AD neuropathology. However, gamma-aminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, and Aβ decreases synaptic glutamatergic transmission to decrease neural network activity. ⋯ Here we describe the roles played by excitatory neurons and GABA inhibitory interneurons in Aβ-induced cognitive deficits and how altered GABA interneurons regulate AD neuropathology. We also comprehensively review recent studies on how GABA interneurons and GABA receptors can be exploited for therapeutic benefit. GABA interneurons are an emerging therapeutic target in AD, with further clinical trials urgently warranted.
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Frontiers in neuroscience · Jan 2020
ReviewCircadian and Sleep Dysfunctions in Neurodegenerative Disorders-An Update.
Disruptions of sleep and circadian rhythms are among the most debilitating symptoms in patients with neurodegenerative diseases. Their underlying pathophysiology is multilayered and multifactorial. Recent evidence suggests that sleep and circadian disturbances may influence the neurodegenerative processes as well as be their consequence. In this perspective, we provide an update of the current understanding of sleep and circadian dysregulation in Alzheimer's, Parkinson's, and Huntington's diseases.
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Frontiers in neuroscience · Jan 2020
Safety and Efficacy of Magnetic Resonance-Guided Focused Ultrasound Surgery With Autofocusing Echo Imaging.
Magnetic resonance-guided focused ultrasound surgery (MRgFUS) lesioning is a new treatment for brain disorders. However, the skull is a major barrier of ultrasound sonication in MRgFUS because it has an irregular surface and varies its size and shape among individuals. We recently developed the concept of skull density ratio (SDR) to select candidates for MRgFUS from among patients with essential tremor (ET). However, SDR is not the only factor contributing to successful MRgFUS lesioning treatment-refining the target through exact measurement of the ultrasonic echo in the transducer also improves treatment efficacy. In the present study, we carried out MRgFUS lesioning using an autofocusing echo imaging technique. We aimed to evaluate the safety and efficacy of this new approach, especially in patients with low SDR in whom previous focusing methods have failed. ⋯ clinicaltrials.gov, identifier: NCT03935581.
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Frontiers in neuroscience · Jan 2020
Cutaneous Aβ-Non-nociceptive, but Not C-Nociceptive, Dorsal Root Ganglion Neurons Exhibit Spontaneous Activity in the Streptozotocin Rat Model of Painful Diabetic Neuropathy in vivo.
Diabetic peripheral neuropathic pain (DPNP) is the most devastating complication of diabetes mellitus. Unfortunately, successful therapy for DPNP remains a challenge because its pathogenesis is still elusive. ⋯ Compared with control, we found in STZ-rats with established pain hypersensitivity (5 weeks post-STZ) several significant changes including: (a) A 23% increase in the incidence of spontaneous activity (SA) in Aβ-LTMs (but not C-mechanosensitive nociceptors) that may cause dysesthesias/paresthesia suffered by DPNP patients, (b) membrane hyperpolarization and a ∼85% reduction in SA rate in Aβ-LTMs by Kv7 channel activation with retigabine (6 mg/kg, i.v.) suggesting that Kv7/M channels may be involved in mechanisms of SA generation in Aβ-LTMs, (c) decreases in AP duration and in duration and amplitude of afterhyperpolarization (AHP) in C-and/or Aβ-nociceptors. These faster AP and AHP kinetics may lead to repetitive firing and an increase in afferent input to the CNS and thereby contribute to DPNP development, and (d) a decrease in the electrical thresholds of Aβ-nociceptors that may contribute to their sensitization, and thus to the resulting hypersensitivity associated with DPNP.
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Frontiers in neuroscience · Jan 2020
Spinal Mobilization Prevents NGF-Induced Trunk Mechanical Hyperalgesia and Attenuates Expression of CGRP.
Low back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies. Spinal mobilization (SM) is a non-pharmacological approach recommended by most clinical guidelines for LBP, but greater utilization and treatment optimization are hampered by a lack of mechanistic knowledge underlying its hypoalgesic clinical effects. ⋯ SM prevents the development of local (trunk) NGF-induced mechanical hyperalgesia and distant (hindpaw) allodynia, in part, through attenuation of CGRP expression in lumbar DRG sensory neurons. NGF decreases rat exploratory behavior and increases spontaneous pain for which passive SM acts to mitigate these pain-related behavioral changes. These initial study findings suggest that beginning daily SM soon after injury onset might act to minimize or prevent the development of LBP by reducing production of pain-related neuropeptides.