Sleep disturbances in Alzheimer's and Parkinson's diseases.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders and exact a burden on our society greater than cardiovascular disease and cancer combined. While cognitive and motor symptoms are used to define AD and PD, respectively, patients with both disorders exhibit sleep disturbances including insomnia, hypersomnia and excessive daytime napping. The molecular basis of perturbed sleep in AD and PD may involve damage to hypothalamic and brainstem nuclei that control sleep-wake cycles. Perturbations in neurotransmitter and hormone signaling (e.g., serotonin, norepinephrine and melatonin) and the neurotrophic factor BDNF likely contribute to the disease process. Abnormal accumulations of neurotoxic forms of amyloid ß-peptide, tau and α-synuclein occur in brain regions involved in the regulation of sleep in AD and PD patients, and are sufficient to cause sleep disturbances in animal models of these neurodegenerative disorders. Disturbed regulation of sleep often occurs early in the course of AD and PD, and may contribute to the cognitive and motor symptoms. Treatments that target signaling pathways that control sleep have been shown to retard the disease process in animal models of AD and PD, suggesting a potential for such interventions in humans at risk for or in the early stages of these disorders.

Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF.

Ceruloplasmin (Cp) is a ferroxidase involved in iron metabolism by converting Fe(2+) to Fe(3+), and by regulating cellular iron efflux. In the ceruloplasmin knockout (CpKO) mouse, the deregulation of iron metabolism results in moderate liver and spleen hemosiderosis, but the impact of Cp deficiency on brain neurochemistry and behavior in this animal model is unknown. We found that in contrast to peripheral tissues, iron levels in the hippocampus are significantly reduced in CpKO mice. Although it does not cause any discernable deficits in motor function or learning and memory, Cp deficiency results in heightened anxiety-like behavior in the open field and elevated plus maze tests. This anxiety phenotype is associated with elevated levels of plasma corticosterone. Previous studies provided evidence that anxiety disorders and long-standing stress are associated with reductions in levels of serotonin (5HT) and brain-derived neurotrophic factor (BDNF) in the hippocampus. We found that levels of 5HT and norepinephrine (NE), and the expression of BDNF and its receptor trkB, are significantly reduced in the hippocampus of CpKO mice. Thus, Cp deficiency causes an anxiety phenotype by a mechanism that involves decreased levels of iron, 5HT, NE, and BDNF in the hippocampus.

Inflammatory cytokine and chemokine expression is differentially modulated acutely in the dorsal root ganglion in response to different nerve root compressions.

STUDY DESIGN: Inflammatory proteins were quantified in bilateral dorsal root ganglions (DRGs) at 1 hour and 1 day using a multiplexed assay after 2 different unilateral nerve root compression injuries. OBJECTIVE: To quantify cytokines and a chemokine in the DRG after nerve root compression with and without a chemical injury to determine contributing inflammatory factors in the DRG that may mediate radicular nociception in clinically relevant nerve root pathologies. SUMMARY OF BACKGROUND DATA: Inflammatory cytokines are known to relate to the behavioral hypersensitivity induced after injuries to the nerve root. However, the relative expression of these proteins in the DRG after cervical nerve root compression are not known. METHODS: The right C7 nerve root underwent transient compression (10 gf) or transient compression with a chemical irritation (10 gf + chr). The chemical injury was also given alone (chr), and the nerve root was exposed (sham), providing 2 types of controls. Mechanical allodynia was measured to assess behavioral outcomes. Interleukin (IL)-1b, IL-6, tumor necrosis factor-a, and macrophage inflammatory protein 3 (MIP3) were quantified in bilateral DRGs at 1 hour and 1 day using a multiplexed assay. RESULTS: Ipsilateral allodynia at day 1 after 10 gf + chr was significantly increased over both 10 gf and chr (P < 0.049). Cytokines and MIP3 were not statistically increased over sham at 1 hour. By day 1 after 10 gf + chr, all proteins (IL-1ß, IL-6, tumor necrosis factor-a, MIP3) were significantly increased over both normal and sham in the ipsilateral DRG (P < 0.036), and the cytokines were also significantly increased over chr (P < 0.029). Despite allodynia at day 1, cytokines at that time were not increased over normal or sham after either 10 gf or chr. CONCLUSION: Nerve root compression alone may not be sufficient to induce early increases in proinflammatory cytokines in the DRG after radiculopathy and this early protein response may not be directly responsible for nociception in this type of injury.

Cytokine antagonism reduces pain and modulates spinal astrocytic reactivity after cervical nerve root compression.

Relationships between nerve root compression, behavioral sensitivity, spinal cytokines, and glial reactivity are not fully defined for painful cervical nerve root compression. Spinal cytokines were quantified after mechanical root compression (10gf), root exposure to inflammatory chromic gut material (chr), the combination of both insults together (10gf + chr) or sham. TNFalpha and IL-1beta significantly increased at 1 h (p < 0.029). IL-1alpha was significantly increased over normal, sham and chr at 1 h following 10gf and over normal and sham after 10gf + chr (p < 0.048). By day 1, only IL-1beta after 10gf remained elevated over normal (p = 0.038). Accordingly, the soluble TNF receptor-1 (sTNFR1) and the IL-1 receptor antagonist (IL-1ra) were separately administered at early time points after each injury. With sTNFR1, behavioral sensitivity was significantly decreased for 7 days after both 10gf and 10gf + chr (p < 0.005). Treatment with IL-1ra significantly reduced sensitivity for 10gf + chr (p < 0.034) but not for 10gf. Sensitivity remained significantly elevated over sham at all time points (p < 0.044). Spinal astrocytic reactivity significantly decreased for both treatments after 10gf (p < 0.002); but, only IL-1ra following 10gf + chr significantly reduced astrocytic reactivity (p < 0.001). Early increases in spinal TNFalpha, IL-1beta, and IL-1alpha may induce pain, affect spinal astrocytic responses, and appear to have differential effects in mediating the behavioral hypersensitivity produced by different types of painful cervical radicular injuries.

Cytokine mRNA expression in painful radiculopathy.

UNLABELLED: Inflammatory cytokines contribute to lumbar radiculopathy. Regulation of cytokines for transient cervical injuries, with or without longer-lasting inflammation, remains to be defined. The C7 root in the rat underwent compression (10gf), chromic gut suture exposure (chr), or their combination (10gf+chr). Ipsilateral C7 spinal cord and dorsal root ganglia (DRG) were harvested at 1 hour after injury for real-time PCR analysis of IL-1beta, IL-6, and TNF-alpha. Cytokine mRNA increased after all 3 injuries. TNF-alpha mRNA in the DRG was significantly increased over sham after 10gf+chr (P = .026). Spinal IL-1beta was significantly increased over sham after 10gf and 10gf+chr (P < .024); IL-6 was significantly increased after 10gf+chr (P < .024). In separate studies, the soluble TNF-alpha receptor was administered at injury and again at 6 hours in all injury paradigms. Allodynia was assessed and tissue samples were harvested for cytokine PCR. Allodynia significantly decreased with receptor administration for 10gf and 10gf+chr (P < .005). Treatment also significantly decreased IL-1beta and TNF-alpha mRNA in the DRG for 10gf+chr (P < .028) at day 1. Results indicate an acute, robust cytokine response in cervical nerve root injury with varying patterns, dependent on injury type, and that early increases in TNF-alpha mRNA in the DRG may drive pain-related signaling for transient cervical injuries. PERSPECTIVE: Inflammatory cytokine mRNA in the DRG and spinal cord are defined after painful cervical nerve root injury. Studies describe a role for TNF-alpha in mediating behavioral sensitivity and inflammatory cytokines in transient painful radiculopathy. Results outline an early response of inflammatory cytokine upregulation in cervical pain.

Spinal neuropeptide responses in persistent and transient pain following cervical nerve root injury.

STUDY DESIGN: Behavioral and immunohistochemical analysis in rat models of persistent and transient allodynia. OBJECTIVES: To examine separate cervical nerve root injuries (compression, transection) for producing behavioral hypersensitivity and investigate spinal neuropeptides to understand relationships to pain symptoms. SUMMARY OF BACKGROUND DATA: Mechanical cervical nerve root injury can be a source of neck pain. Painful lumbar radiculopathy models show that different nerve root ligation intensities produce differential allodynia responses. Spinal neuropeptides can mediate pain responses. Yet, little is known about their contributions to pain in the cervical spine. METHODS: Rats underwent separate procedures on the right C7 nerve roots: transection (n = 12), 10-gf compression for 15 minutes (n = 11), or sham (n = 5). Ipsilateral forepaw mechanical allodynia was measured after surgery for 7 days. C7 spinal cord tissue was analyzed by immunohistochemistry for substance P and calcitonin gene-related peptide (CGRP) expression on days 1 and 7 for each injury; densitometry quantified immunoreactivity in lamina I of the ipsilateral dorsal horn. RESULTS: Both injuries immediately produced significant increases in allodynia. Sensitivity was sustained following root compression, and at day 7, was not different from day 1. By day 7 after transection, allodynia had returned to baseline and sham levels, significantly decreasing from day 1 (P = 0.0012). Spinal substance P and CGRP were increased over normal at day 1 for both injuries and decreased with time for CGRP after transection, which paralleled behaviors. For individual rats, substance P was significantly (P < 0.001) correlated with CGRP expression for both injuries. CONCLUSIONS: Compression and transection of the cervical nerve root produce different forepaw allodynia responses, with persistent and transient sensitivity, respectively. Spinal neuropeptide expression in these models parallels this sensitivity, suggesting their potential role in pain symptoms.