Mitochondrial Health, Physical Functioning, and Daily Affect: Bioenergetic Mechanisms of Dementia Caregiver Well-Being.

OBJECTIVE: Chronic stress adversely affects mental and physical well-being. However, health outcomes vary among people experiencing the same stressor. Individual differences in physical and emotional well-being may depend on mitochondrial biology, as energy production is crucial for stress regulation. This study investigated whether mitochondrial respiratory capacity corresponds to individual differences in dementia spousal caregivers' mental and physical health. METHODS: Spousal caregivers of individuals with Alzheimer's disease and related dementias ( N = 102, mean age = 71, 78% female, 83% White) provided peripheral blood samples and completed self-report questionnaires on quality of life, caregiver burden, and a 7-day affect scale. Multiple and mixed linear regressions were used to test the relationship between mitochondrial biology and well-being. RESULTS: Spare respiratory capacity ( b = 12.76, confidence interval [CI] = 5.23-20.28, p = .001), maximum respiratory capacity ( b = 8.45, CI = 4.54-12.35, p < .0001), and ATP-linked respiration ( b = 10.11, CI = 5.05-15.18, p = .0001) were positively associated with physical functioning. At average ( b = -2.23, CI = -3.64 to -0.82, p = .002) and below average ( b = -4.96, CI = -7.22 to 2.70, p < .0001) levels of spare respiratory capacity, caregiver burden was negatively associated with daily positive affect. At above average levels of spare respiratory capacity, caregiver burden was not associated with positive affect ( p = .65). CONCLUSIONS: Findings suggest that higher mitochondrial respiratory capacity is associated with better psychological and physical health-a pattern consistent with related research. These findings provide some of the earliest evidence that cellular bioenergetics are related to well-being.

Upregulation of delta opioid receptor by meningeal interleukin-10 prevents relapsing pain.

Chronic pain often includes periods of transient amelioration and even remission that alternate with severe relapsing pain. While most research on chronic pain has focused on pain development and maintenance, there is a critical unmet need to better understand the mechanisms that underlie pain remission and relapse. We found that interleukin (IL)-10, a pain resolving cytokine, is produced by resident macrophages in the spinal meninges during remission from pain and signaled to IL-10 receptor-expressing sensory neurons. Using unbiased RNA-sequencing, we identified that IL-10 upregulated expression and antinociceptive activity of δ-opioid receptor (δOR) in the dorsal root ganglion. Genetic or pharmacological inhibition of either IL-10 signaling or δOR triggered relapsing pain. Overall, our findings, from electrophysiology, genetic manipulation, flow cytometry, pharmacology, and behavioral approaches, indicate that remission of pain is not simply a return to the naïve state. Instead, remission is an adapted homeostatic state associated with lasting pain vulnerability resulting from persisting neuroimmune interactions within the nociceptive system. Broadly, this sheds light on the elusive mechanisms underlying recurrence a common aspect across various chronic pain conditions.

HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling.

Peripheral neuropathic pain induced by the chemotherapeutic cisplatin can persist for months to years after treatment. Histone deacetylase 6 (HDAC6) inhibitors have therapeutic potential for cisplatin-induced neuropathic pain since they persistently reverse mechanical hypersensitivity and spontaneous pain in rodent models. Here, we investigated the mechanisms underlying reversal of mechanical hypersensitivity in male and female mice by a 2 week treatment with an HDAC6 inhibitor, administered 3 d after the last dose of cisplatin. Mechanical hypersensitivity in animals of both sexes treated with the HDAC6 inhibitor was temporarily reinstated by a single injection of the neutral opioid receptor antagonist 6ß-naltrexol or the peripherally restricted opioid receptor antagonist naloxone methiodide. These results suggest that tonic peripheral opioid ligand-receptor signaling mediates reversal of cisplatin-induced mechanical hypersensitivity after treatment with an HDAC6 inhibitor. Pointing to a specific role for δ opioid receptors (DORs), Oprd1 expression was decreased in DRG neurons following cisplatin administration, but normalized after treatment with an HDAC6 inhibitor. Mechanical hypersensitivity was temporarily reinstated in both sexes by a single injection of the DOR antagonist naltrindole. Consistently, HDAC6 inhibition failed to reverse cisplatin-induced hypersensitivity when DORs were genetically deleted from advillin+ neurons. Mechanical hypersensitivity was also temporarily reinstated in both sexes by a single injection of a neutralizing antibody against the DOR ligand met-enkephalin. In conclusion, we reveal that treatment with an HDAC6 inhibitor induces tonic enkephalin-DOR signaling in peripheral sensory neurons to suppress mechanical hypersensitivity.SIGNIFICANCE STATEMENT Over one-fourth of cancer survivors suffer from intractable painful chemotherapy-induced peripheral neuropathy (CIPN), which can last for months to years after treatment ends. HDAC6 inhibition is a novel strategy to reverse CIPN without negatively interfering with tumor growth, but the mechanisms responsible for persistent reversal are not well understood. We built on evidence that the endogenous opioid system contributes to the spontaneous, apparent resolution of pain caused by nerve damage or inflammation, referred to as latent sensitization. We show that blocking the δ opioid receptor or its ligand enkephalin unmasks CIPN in mice treated with an HDAC6 inhibitor (latent sensitization). Our work provides insight into the mechanisms by which treatment with an HDAC6 inhibitor apparently reverses CIPN.

Chronic restraint stress impairs voluntary wheel running but has no effect on food-motivated behavior in mice.

Chronic restraint stress is known to cause significant alterations of mitochondrial biology. However, its effects on effort-based behavior and the sensitivity of these effects to treatments that restore mitochondrial function have not been assessed. Based on the hypothesis that the behavioral consequences of this stressor should be more severe for an energy demanding activity than for an energy procuring activity, we compared the effects of chronic restraint stress on the performance of male mice trained to use a running wheel or to nose poke for a food reward in an operant conditioning cage. In accordance with our hypothesis, we observed that exposure of mice to 2-hour daily restraint sessions for 14 to 16 days during the light phase of the cycle reliably decreased voluntary wheel running but had no effect on working for food in a fixed ratio 10 schedule of food reinforcement or in a progressive ratio schedule of food reinforcement. This dissociation between the two types of behavioral activities could reflect an adaptive response to the constraint imposed by chronic restraint stress on mitochondria function and its negative consequences on energy metabolism. To determine whether it is the case, we administered mesenchymal stem cells intranasally to chronically restrained mice to repair the putative mitochondrial dysfunction induced by chronic restraint stress. This intervention had no effect on wheel running deficits. Assessment of mitochondrial gene expression in the brain of mice submitted to chronic restraint stress revealed an increase in the expression of genes involved in mitochondrial biology that showed habituation with repetition of daily sessions of restraint stress. These original findings can be interpreted to indicate that chronic restraint stress induces behavioral and mitochondrial adjustments that contribute to metabolic adaptation to this stressor and maintain metabolic flexibility.

Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206+ myeloid cells.

Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund's Adjuvant inflammatory pain model, we show that Pi16-/- mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain. In contrast to neuropathic pain models, we did not observe any changes in blood-nerve barrier permeability due to PI16 deletion. Instead, Pi16-/- mice display reduced macrophage density in the CFA-injected hindpaw. Furthermore, there was a significant bias toward CD206hi (anti-inflammatory) macrophages in the hindpaw and associated dorsal root ganglia. Following CFA, intrathecal depletion of CD206+ macrophages using mannosylated clodronate liposomes promoted sustained pain in Pi16-/- mice. Similarly, an IL-10 neutralizing antibody also promoted sustained CFA pain in the Pi16-/ when administered intrathecally. Collectively, our results point to fibroblast-derived PI16 mediating substantial differences in macrophage phenotype in the pain neuroaxis under conditions of inflammation. The co-expression of PI16 alongside fibroblast markers in human DRG raise the likelihood that a similar mechanism operates in human inflammatory pain states. Collectively, our findings may have implications for targeting fibroblast-immune cell crosstalk for the treatment of chronic pain.

Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice.

BACKGROUND: There is increasing concern that cancer and cancer treatment accelerate aging and the associated cognitive decline. We showed recently that treatment of 9-month-old male mice with cisplatin causes cognitive deficits that are associated with formation of tau deposits in the hippocampus. Here we explored the capacity of mesenchymal stem cells (MSC) given via the nose to prevent age-related brain tau deposits. Moreover, we more closely examined the cellular distribution of this hallmark of accelerated brain aging in response to treatment of 9-month-old female and male mice with cisplatin. RESULTS: We show that cisplatin induces tau deposits in the entorhinal cortex and hippocampus in both sexes. The tau deposits colocalize with syndecan-2. Astrocytes surrounding tau deposits have increased glial fibrillary acidic protein glial fibrillary acidic protein (GFAP) expression. Most of the cisplatin-induced tau deposits were located in microtubule associated protein-2 (MAP-2)+ neurons that were surrounded by aquaporin 4+ (AQP4)+ neuron-facing membrane domains of astrocytes. In addition, some tau deposits were detected in the perinuclear region of GFAP+ astrocytes and in CD31+ endothelial cells. There were no morphological signs of activation of ionized calcium binding adaptor molecule-1+ (Iba-1)+ microglia and no increases in brain cytokine production. Nasal administration of MSC at 48 and 96 hours after cisplatin prevented formation of tau deposits and normalized syndecan-2 and GFAP expression. Behaviorally, cisplatin-induced tau cluster formation was associated with reduced executive functioning and working/spatial memory and nasal administration of MSC at 48 and 96 hours after cisplatin prevented these cognitive deficits. Notably, delayed MSC administration (1 month after cisplatin) also prevented tau cluster formation and cognitive deficits, in both sexes. CONCLUSION: In summary, nasal administration of MSC to older mice at 2 days or 1 month after completion of cisplatin treatment prevents the accelerated development of tau deposits in entorhinal cortex and hippocampus and the associated cognitive deficits. Since MSC are already in clinical use for many other clinical indications, developing nasal MSC administration for treatment of accelerated brain aging and cognitive deficits in cancer survivors should be feasible and would greatly improve their quality of life.

The fibroblast-derived protein PI16 controls neuropathic pain.

Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here, we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury (SNI) model of neuropathic pain increases PI16 protein levels in fibroblasts in dorsal root ganglia (DRG) meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG, and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes transendothelial leukocyte migration. In vivo, Pi16-/- mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK, and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross-talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx, and increased pain. Its key role in neuropathic pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.

Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment.

Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca2+ signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain.

An HDAC6 inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway.

Chemotherapy-induced peripheral neuropathy (CIPN) impacts a growing number of cancer survivors and treatment options are limited. Histone deacetylase 6 (HDAC6) inhibitors are attractive candidates because they reverse established CIPN and may enhance anti-tumor effects of chemotherapy. Before considering clinical application of HDAC6 inhibitors, the mechanisms underlying reversal of CIPN need to be identified. We showed previously that deletion of Hdac6 from sensory neurons did not prevent cisplatin-induced mechanical hypersensitivity, while global deletion of Hdac6 was protective, indicating involvement of HDAC6 in other cell types. Here we show that local depletion of MRC1 (CD206)-positive macrophages without affecting microglia by intrathecal administration of mannosylated clodronate liposomes reduced the capacity of an HDAC6 inhibitor to reverse cisplatin-induced mechanical hypersensitivity. The HDAC6 inhibitor increased spinal cord Il10 mRNA and this was M2-macrophage dependent. Intrathecal administration of anti-IL-10 antibody or genetic deletion of Il10 prevented resolution of mechanical hypersensitivity. Genetic deletion of the IL-10 receptor from Advillin+ neurons prevented resolution of mechanical hypersensitivity in mice treated with the HDAC6 inhibitor. These findings indicate that treatment with an HDAC6 inhibitor increases macrophage-derived IL-10 signaling to IL-10 receptors on Advillin+ sensory neurons to resolve mechanical hypersensitivity. Cisplatin decreases mitochondrial function in sensory axons, and HDAC6 inhibition can promote axonal transport of healthy mitochondria. Indeed, the HDAC6 inhibitor normalized cisplatin-induced tibial nerve mitochondrial deficits. However, this was independent of macrophages and IL-10 signaling. In conclusion, our findings indicate that administration of an HDAC6 inhibitor reverses cisplatin-induced mechanical hypersensitivity through two complementary pathways: macrophage HDAC6 inhibition to promote IL-10 production and IL-10 signaling to DRG neurons, and neuronal HDAC6 inhibition to restore axonal mitochondrial health.

Nasal administration of mesenchymal stem cells reverses chemotherapy-induced peripheral neuropathy in mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequently reported adverse effects of cancer treatment. CIPN often persists long after treatment completion and has detrimental effects on patient's quality of life. There are no efficacious FDA-approved drugs for CIPN. We recently demonstrated that nasal administration of mesenchymal stem cells (MSC) reverses the cognitive deficits induced by cisplatin in mice. Here we show that nasal administration of MSC after cisplatin- or paclitaxel treatment- completely reverses signs of established CIPN, including mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. Nasally administered MSC enter rapidly the meninges of the brain, spinal cord and peripheral lymph nodes to promote IL-10 production by macrophages. MSC-mediated resolution of mechanical allodynia, recovery of IENFs and restoration of DRG mitochondrial function critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, WT MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons. In conclusion, only two nasal administrations of MSC fully reverse CIPN and the associated mitochondrial abnormalities via an IL-10 dependent pathway. Since MSC are already applied clinically, we propose that nasal MSC treatment could become a powerful treatment for the large group of patients suffering from neurotoxicities of cancer treatment.

Identification of FAM173B as a protein methyltransferase promoting chronic pain.

Chronic pain is a debilitating problem, and insights in the neurobiology of chronic pain are needed for the development of novel pain therapies. A genome-wide association study implicated the 5p15.2 region in chronic widespread pain. This region includes the coding region for FAM173B, a functionally uncharacterized protein. We demonstrate here that FAM173B is a mitochondrial lysine methyltransferase that promotes chronic pain. Knockdown and sensory neuron overexpression strategies showed that FAM173B is involved in persistent inflammatory and neuropathic pain via a pathway dependent on its methyltransferase activity. FAM173B methyltransferase activity in sensory neurons hyperpolarized mitochondria and promoted macrophage/microglia activation through a reactive oxygen species-dependent pathway. In summary, we uncover a role for methyltransferase activity of FAM173B in the neurobiology of pain. These results also highlight FAM173B methyltransferase activity as a potential therapeutic target to treat debilitating chronic pain conditions.

GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity.

Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2+/- mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile. Low levels of myeloid GRK2 confer protection against hepatic insulin resistance, steatosis and inflammation. In adipose tissue, pro-inflammatory cytokines are reduced and insulin signaling is preserved. Macrophages from LysM-GRK2+/- mice secrete less pro-inflammatory cytokines when stimulated with lipopolysaccharide (LPS) and their conditioned media has a reduced pathological influence in cultured adipocytes or naïve bone marrow-derived macrophages. Our data indicate that reducing GRK2 levels in myeloid cells, by attenuating pro-inflammatory features of macrophages, has a relevant impact in adipose-liver crosstalk, thus preventing high fat diet-induced metabolic alterations.

A central role for apathy in the effectiveness of interventions for cancer-related fatigue.

OBJECTIVE: Cancer-related fatigue (CRF) affects a substantial number of cancer patients and survivors. Recommendations for CRF treatments are largely based on results of randomized controlled trials. The interpretability of such results is limited to patients eligible and willing to participate in these trials. We aimed to address this limitation in a retrospective study of patients seen at a CRF clinic in a comprehensive cancer center. The objectives were to (a) determine the effectiveness of clinician-initiated interventions for CRF and identify their mediators and (b) describe the frequency and effectiveness of patient-initiated physical activity (PA) behavior for alleviating CRF and identify determinants of this PA. METHODS: Data (patient-reported somatic and mood symptoms; clinical data; clinician-documented changes in medication and behavior) from n = 213 patients collected as part of the clinic's standard of care at initial clinical consult and follow-up 4 to 11 weeks later were included. Effects of clinician-initiated interventions and patient-initiated PA on change in fatigue were analyzed using linear models. RESULTS: Of all clinician-initiated interventions, only psychostimulant start was recorded frequent enough for further investigation and was associated with reduced fatigue; this association was mediated by a reduction in apathy. PA was also associated with reduced fatigue severity. PA initiation/increase after consult was associated with lower apathy at consult. CONCLUSIONS: These results demonstrate a major role for patient apathy in the effectiveness and initiation of CRF-targeting interventions. Behavioral therapies focusing on reduction in apathy should be considered as initial treatment of CRF in those with substantial apathy.

Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment.

Cancer and its treatment are associated with neurotoxic side effects, including cognitive dysfunction, altered functional connectivity in the brain and structural abnormalities in white matter. There is evidence that cancer and its treatment can accelerate aging. Tau is a microtubule associated protein that contributes to microtubule stability thereby playing a key role in neuronal function. Clustering of tau is commonly observed in the aged brain and is related to cognitive decline. We hypothesized that chemotherapy-induced cognitive impairment is associated with accelerated development of tau clustering in the brain as a sign of accelerated aging. We show for the first time that treatment of adult (7-8 month-old) male C57BL/6 mice with cisplatin results in reduced cognitive function and a marked increase in the number of large endogenous tau clusters in the hippocampus when assessed 4 months later. In contrast, we detected only few small tau clusters in the hippocampus of age-matched 11-12 month-old control mice. Astrocyte GFAP expression was increased in close vicinity to the tau clusters in cisplatin-treated mice. We did not detect changes in the microglial marker Iba-1 in the brain of mice treated with cisplatin. The accelerated formation of Tau-1 clusters in cisplatin-treated mice was associated with a decrease in the levels of the post-synaptic marker PSD95 and of the presynaptic marker synaptophysin in the hippocampus. We demonstrate here for the first time that chemotherapy markedly accelerates development of signs of tauopathy and loss of synaptic integrity in the hippocampus. These findings provide a mechanistic link between chemotherapy cognitive decline and accelerated aging in cancer survivors.

Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1.

cAMP signaling plays a key role in regulating pain sensitivity. Here, we uncover a previously unidentified molecular mechanism in which direct phosphorylation of the exchange protein directly activated by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibiting persistent inflammatory pain. Epac1(-/-) mice are protected against inflammatory hyperalgesia in the complete Freund's adjuvant (CFA) model. Moreover, the Epac-specific inhibitor ESI-09 inhibits established CFA-induced mechanical hyperalgesia without affecting normal mechanical sensitivity. At the mechanistic level, CFA increased activity of the Epac target Rap1 in dorsal root ganglia of WT, but not of Epac1(-/-), mice. Using sensory neuron-specific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA-induced hyperalgesia in a kinase activity-dependent manner. In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation of Epac1 at Ser-108 in the Disheveled/Egl-10/pleckstrin domain. This phosphorylation event inhibits agonist-induced translocation of Epac1 to the plasma membrane, thereby reducing Rap1 activation. Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechanosensor Piezo2 and that Piezo2 contributes to inflammatory mechanical hyperalgesia. Collectively, these findings identify a key role of Epac1 in chronic inflammatory pain and a molecular mechanism for controlling Epac1 activity and chronic pain through phosphorylation of Epac1 at Ser-108. Importantly, using the Epac inhibitor ESI-09, we validate Epac1 as a potential therapeutic target for chronic pain.

Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism-like behavior in a rat model of diffuse white matter injury.

Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism-spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple-hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long-term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism-like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants.

Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is important to note that such interventions should not interfere with the antitumor effects of chemotherapy. Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy "currency" adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Herein, the authors discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-µ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system. Cancer 2018;124:2289-98. © 2018 American Cancer Society.

Attachment and telomere length: more evidence for psychobiological connections between close relationships, health, and aging.

Individuals with a history of poor interpersonal relationships are more likely to demonstrate negative health outcomes than those who have had high quality relationships. We sought to evaluate how attachment orientations, stress-induced respiratory sinus arrhythmia (RSA), and self-reported stress were associated with length of telomeres measured from peripheral blood mononuclear cells. Participants (N = 213) completed self-report measures of attachment and stress. Measurement of RSA was conducted before and after a stressful task and a blood draw was completed for analysis of telomere length. Attachment orientations were not directly associated with telomere length; however, we found that high attachment anxiety was associated with shorter length of telomeres via high self-reported stress. Attachment avoidance was also associated with telomere length via self-reported stress, but only among those with high stress-induced RSA. Exploratory analyses of T cell subsets indicated that stress was most strongly associated with telomeres from CD8CD28+ cells in comparison to CD8CD28- and CD4 cells. Study findings indicate that attachment orientations are associated with telomere length via stress, providing novel insights into the mechanisms through which close relationships can impact health and aging.

CD8+ T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain.

Chemotherapy-induced peripheral neuropathy (CIPN), characterized by pain and numbness in hands and feet, is a common side effect of cancer treatment. In most patients, symptoms of CIPN subside after treatment completion. However, in a substantial subgroup, CIPN persists long into survivorship. Impairment in pain resolution pathways may explain persistent CIPN. We investigated the contribution of T cells and endogenous interleukin (IL)-10 to resolution of CIPN. Paclitaxel-induced mechanical allodynia was prolonged in T-cell-deficient (Rag1-/-) mice compared with wild-type (WT) mice. There were no differences between WT and Rag1-/- mice in severity of paclitaxel-induced mechanical allodynia. Adoptive transfer of either CD3+ or CD8+, but not CD4+, T cells to Rag1-/- mice normalized resolution of CIPN. Paclitaxel treatment increased the number of T cells in lumbar dorsal root ganglia (DRG), where CD8+ T cells were the major subset. Inhibition of endogenous IL-10 signaling by intrathecal injection of anti-IL-10 to WT mice or Rag1-/- mice reconstituted with CD8+ T cells delayed recovery from paclitaxel-induced mechanical allodynia. Recovery was also delayed in IL-10 knock-out mice. Conversely, administration of exogenous IL-10 attenuated paclitaxel-induced allodynia. In vitro, IL-10 suppressed abnormal paclitaxel-induced spontaneous discharges in DRG neurons. Paclitaxel increased DRG IL-10 receptor expression and this effect requires CD8+ T cells. In conclusion, we identified a novel mechanism for resolution of CIPN that requires CD8+ T cells and endogenous IL-10. We propose that CD8+ T cells increase DRG IL-10 receptor expression and that IL-10 suppresses the abnormal paclitaxel-induced spontaneous discharges by DRG neurons to promote recovery from CIPN. SIGNIFICANCE STATEMENT: Chemotherapy-induced peripheral neuropathy persists after completion of cancer treatment in a significant subset of patients, whereas others recover. Persistent neuropathy after completion of cancer treatment severely affects quality of life. We propose that understanding how neuropathy resolves will identify novel avenues for treatment. We identified a novel and critical role for CD8+ T cells and for endogenous IL-10 in recovery from paclitaxel-induced neuropathy in mice. Enhancing the capacity of CD8+ T cells to promote resolution or increasing IL-10 signaling are promising targets for novel interventions. Clinically, peripheral blood CD8+ T-cell function and/or the capacity of individuals to produce IL-10 may represent biomarkers of risk for developing persistent peripheral neuropathy after completion of cancer treatment.

IL4-10 Fusion Protein Is a Novel Drug to Treat Persistent Inflammatory Pain.

UNLABELLED: Chronic pain is a major clinical problem that is difficult to treat and requires novel therapies. Although most pain therapies primarily target neurons, neuroinflammatory processes characterized by spinal cord and dorsal root ganglion production of proinflammatory cytokines play an important role in persistent pain states and represent potential therapeutic targets. Anti-inflammatory cytokines are attractive candidates to regulate aberrant neuroinflammatory processes, but the therapeutic potential of these cytokines as stand-alone drugs is limited. Their optimal function requires concerted actions with other regulatory cytokines, and their relatively small size causes rapid clearance. To overcome these limitations, we developed a fusion protein of the anti-inflammatory cytokines interleukin 4 (IL4) and IL10. The IL4-10 fusion protein is a 70 kDa glycosylated dimeric protein that retains the functional activity of both cytokine moieties. Intrathecal administration of IL4-10 dose-dependently inhibited persistent inflammatory pain in mice: three IL4-10 injections induced full resolution of inflammatory pain in two different mouse models of persistent inflammatory pain. Both cytokine moieties were required for optimal effects. The IL4-10 fusion protein was more effective than the individual cytokines or IL4 plus IL10 combination therapy and also inhibited allodynia in a mouse model of neuropathic pain. Mechanistically, IL4-10 inhibited the activity of glial cells and reduced spinal cord and dorsal root ganglion cytokine levels without affecting paw inflammation. In conclusion, we developed a novel fusion protein with improved efficacy to treat pain, compared with wild-type anti-inflammatory cytokines. The IL4-10 fusion protein has potential as a treatment for persistent inflammatory pain. SIGNIFICANCE STATEMENT: The treatment of chronic pain is a major clinical and societal challenge. Current therapies to treat persistent pain states are limited and often cause major side effects. Therefore, novel analgesic treatments are urgently needed. In search of a novel drug to treat chronic pain, we developed a fusion protein consisting of two prototypic regulatory cytokines, interleukin 4 (IL4) and IL10. The work presented in this manuscript shows that this IL4-10 fusion protein overcomes some major therapeutic limitations of pain treatment with individual cytokines. The IL4-10 fusion protein induces full resolution of persistent inflammatory pain in two different mouse models. These novel findings are significant, as they highlight the IL4-10 fusion protein as a long-needed potential new drug to stop persistent pain states.