Brain, behavior, and immunity
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Brain Behav. Immun. · Jul 2018
Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.
N-type voltage-gated calcium (Cav2.2) channels are expressed in the central terminals of dorsal root ganglion (DRG) neurons, and are critical for neurotransmitter release. Cav2.2 channels are also expressed in the soma of DRG neurons, where their function remains largely unknown. Here, we showed that Cav2.2 was upregulated in the soma of uninjured L4 DRG neurons, but downregulated in those of injured L5 DRG neurons following L5 spinal nerve ligation (L5-SNL). ⋯ Intrathecal injection of IL-1β induced mechanical allodynia and Cav2.2 upregulation in bilateral L4-6 DRGs of naïve rats, whereas injection of IL-10 substantially prevented mechanical allodynia and Cav2.2 upregulation in L4 DRGs in L5-SNL rats. Finally, in cultured DRG neurons, Cav2.2 was dose-dependently upregulated by IL-1β and downregulated by IL-10. These data indicate that the upregulation of Cav2.2 in uninjured DRG neurons via IL-1β over-production contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.
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Brain Behav. Immun. · May 2018
Human dorsal root ganglion pulsed radiofrequency treatment modulates cerebrospinal fluid lymphocytes and neuroinflammatory markers in chronic radicular pain.
Radicular pain is a common cause of disability. Traditionally treatment has been either epidural steroid injection providing short-term relief or surgery with associated complications. Pulsed radiofrequency (PRF) applied to the dorsal root ganglion (DRG) is a minimally invasive day-care treatment, which is gaining significant clinical acceptance in a selective group of patients with pure radicular pain. ⋯ Our data revealed significant reductions in CD56+, CD3-, NK cell frequencies (p = 0.03) and IFN-γ levels (p = 0.03) in treatment responders, while CD8+ T cell frequencies (p = 0.02) and IL-6 levels were increased (p = 0.05). IL-17 inversely correlated with post-treatment pain severity score (p = 0.01) and pre and post-treatment pain interference scores (p = 0.03, p = 0.01). These results support the concept that chronic radicular pain is a centrally mediated neuroimmune phenomenon and the mechanism of action of DRG PRF treatment is immunomodulatory.
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Brain Behav. Immun. · May 2018
Cognitive benefits of lithium chloride in APP/PS1 mice are associated with enhanced brain clearance of β-amyloid.
Epidemiological evidence suggests that people with bipolar disorder prescribed lithium exhibit a lower risk of Alzheimer's disease (AD) relative to those prescribed other mood-stabilizing medicines. Lithium chloride (LiCl) reduces brain β-amyloid (Aβ) levels, and the brain clearance of Aβ is reduced in AD. Therefore, the purpose of this study was to assess whether the cognitive benefits of LiCl are associated with enhanced brain clearance of exogenously-administered Aβ. ⋯ While LiCl did not affect plaque-associated Aβ42, soluble Aβ42 levels were reduced by 49.9% in APP/PS1 mice receiving LiCl. The brain clearance of 125I-Aβ42 decreased by 27.8% in APP/PS1 mice, relative to WT mice, however, LiCl treatment restored brain 125I-Aβ42 clearance in APP/PS1 mice to a rate similar to that observed in WT mice. These findings suggest that the cognitive benefits and brain Aβ42 lowering effects of LiCl are associated with enhanced brain clearance of Aβ42, possibly via brain microvascular LRP1 upregulation and increased CSF bulk-flow, identifying a novel mechanism of protection by LiCl for the treatment of AD.
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Brain Behav. Immun. · Mar 2018
Stress disinhibits microglia via down-regulation of CD200R: A mechanism of neuroinflammatory priming.
Exposure to stressors primes the neuroinflammatory and microglial proinflammatory response to subsequent immune challenges, suggesting that stress might attenuate immunoregulatory mechanisms in the CNS microenvironment. CD200:CD200R is a key immunoregulatory signaling dyad that constrains microglial activation, and disruption of CD200:CD200R signaling primes microglia to subsequent immune challenges. Therefore, the present study examined the mediating role of CD200:CD200R signaling in stress-induced microglial priming. ⋯ Indeed, treatment with mCD200Fc prior to stress exposure blocked the stress-induced increase in hippocampal HMGB1. The present study suggests that stress exposure disrupts immunoregulatory mechanisms in the brain, which typically constrain the immune response of CNS innate immune cells. This attenuation of immunoregulatory mechanisms may thus permit a primed activation state of microglia to manifest.
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Brain Behav. Immun. · Feb 2018
Triggering receptor expressed on myeloid cells 2 (TREM2) dependent microglial activation promotes cisplatin-induced peripheral neuropathy in mice.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of many antineoplastic agents. Patients treated with chemotherapy often report pain and paresthesias in a "glove-and-stocking" distribution. Diverse mechanisms contribute to the development and maintenance of CIPN. ⋯ The data demonstrated that cisplatin triggered persistent activation of spinal cord microglia through strengthening TREM2/DAP12 signaling, which further resulted in CIPN. Functional blockage of TREM2 or inhibition of microglia both benefited for cisplatin-induced peripheral neuropathy. Microglial TREM2/DAP12 may serve as a potential target for CIPN intervention.