Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats.

Cancer chemotherapy-induced neuropathic pain is a devastating pain syndrome without effective therapies. We previously reported that rats deficient in complement C3, the central component of complement activation cascade, showed a reduced degree of paclitaxel-induced mechanical allodynia (PIMA), suggesting that complement is integrally involved in the pathogenesis of this model. However, the underlying mechanism was unclear. Complement activation leads to the production of C3a, which mediates inflammation through its receptor C3aR1. In this article, we report that the administration of paclitaxel induced a significantly higher expression level of C3aR1 on dorsal root ganglion (DRG) macrophages and expansion of these macrophages in DRGs in wild-type (WT) compared with in C3aR1 knockout (KO) mice. We also found that paclitaxel induced less severe PIMA, along with a reduced DRG expression of transient receptor potential channels of the vanilloid subtype 4 (TRPV4), an essential mediator for PIMA, in C3aR1 KO than in WT mice. Treating WT mice or rats with a C3aR1 antagonist markedly attenuated PIMA in association with downregulated DRG TRPV4 expression, reduced DRG macrophages expansion, suppressed DRG neuron hyperexcitability, and alleviated peripheral intraepidermal nerve fiber loss. Administration of C3aR1 antagonist to TRPV4 KO mice further protected them from PIMA. These results suggest that complement regulates PIMA development through C3aR1 to upregulate TRPV4 on DRG neurons and promote DRG macrophage expansion. Targeting C3aR1 could be a novel therapeutic approach to alleviate this debilitating pain syndrome.

Genetic variations that influence paclitaxel pharmacokinetics and intracellular effects that may contribute to chemotherapy-induced neuropathy: A narrative review.

Taxanes, particularly paclitaxel and docetaxel, are chemotherapeutic agents commonly used to treat breast cancers. A frequent side effect is chemotherapy-induced peripheral neuropathy (CIPN) that occurs in up to 70% of all treated patients and impacts the quality of life during and after treatment. CIPN presents as glove and stocking sensory deficits and diminished motor and autonomic function. Nerves with longer axons are at higher risk of developing CIPN. The causes of CIPN are multifactorial and poorly understood, limiting treatment options. Pathophysiologic mechanisms can include: (i) disruptions of mitochondrial and intracellular microtubule functions, (ii) disruption of axon morphology, and (iii) activation of microglial and other immune cell responses, among others. Recent work has explored the contribution of genetic variation and selected epigenetic changes in response to taxanes for any insights into their relation to pathophysiologic mechanisms of CIPN20, with the hope of identifying predictive and targetable biomarkers. Although promising, many genetic studies of CIPN are inconsistent making it difficult to develop reliable biomarkers of CIPN. The aims of this narrative review are to benchmark available evidence and identify gaps in the understanding of the role genetic variation has in influencing paclitaxel's pharmacokinetics and cellular membrane transport potentially related to the development of CIPN.

Blockade of Type 2A Protein Phosphatase Signaling Attenuates Complement C1q-Mediated Microglial Phagocytosis of Glutamatergic Synapses Induced by Amyloid Fibrils.

We previously reported the critical involvement of metabotropic GluR1 (mGluR1) signaling in complement C1q-dependent microglial phagocytosis of glutamatergic synapses in a rat model of Alzheimer's disease (AD) injected with amyloid fibrils. Here, we explored the role of type 2A protein phosphatase (type 2A PPase), a key enzyme downstream of mGluR1 signaling, in the pathogenesis of AD in rats. Significant local upregulation of PP2A expression was observed in the hippocampal CA1 after bilateral microinjection of amyloid-beta (Aß1-40) fibrils. Amyloid fibrils induced remarkable dephosphorylation of pFMRP (fragile X mental retardation protein) and C1q upregulation in hippocampal glutamatergic synapses, which was ameliorated by microinjection of type 2A PPase inhibitor okadaic acid (OA). Microinjection of OA further attenuated the microglial phagocytosis of glutamatergic synapses, recovered the hippocampal glutamatergic transmission, and improved the performance in Morris water maze test. These findings demonstrated that dysfunction of type 2A PPase signaling contributed to complement C1q-dependent microglial phagocytosis of glutamatergic synapses and the cognitive impairments in the rat model of AD.

A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol.

Introduction: Taxanes are a class of chemotherapeutics commonly used to treat various solid tumors, including breast and ovarian cancers. Taxane-induced peripheral neuropathy (TIPN) occurs in up to 70% of patients, impacting quality of life both during and after treatment. TIPN typically manifests as tingling and numbness in the hands and feet and can cause irreversible loss of function of peripheral nerves. TIPN can be dose-limiting, potentially impacting clinical outcomes. The mechanisms underlying TIPN are poorly understood. As such, there are limited treatment options and no tools to provide early detection of those who will develop TIPN. Although some patients may have a genetic predisposition, genetic biomarkers have been inconsistent in predicting chemotherapy-induced peripheral neuropathy (CIPN). Moreover, other molecular markers (eg, metabolites, mRNA, miRNA, proteins) may be informative for predicting CIPN, but remain largely unexplored. We anticipate that combinations of multiple biomarkers will be required to consistently predict those who will develop TIPN. Methods: To address this clinical gap of identifying patients at risk of TIPN, we initiated the Genetics and Inflammatory Markers for CIPN (GENIE) study. This longitudinal multicenter observational study uses a novel, multimodal approach to evaluate genomic variation, metabolites, DNA methylation, gene expression, and circulating cytokines/chemokines prior to, during, and after taxane treatment in 400 patients with breast cancer. Molecular and patient reported data will be collected prior to, during, and after taxane therapy. Multi-modal data will be used to develop a set of comprehensive predictive biomarker signatures of TIPN. Conclusion: The goal of this study is to enable early detection of patients at risk of developing TIPN, provide a tool to modify taxane treatment to minimize morbidity from TIPN, and improved patient quality of life. Here we provide a brief review of the current state of research into CIPN and TIPN and introduce the GENIE study design.

Suppression of hippocampal GABAergic transmission impairs memory in rodent models of Alzheimer's disease.

Emerging evidence demonstrates the potential involvement of hippocampal GABAergic transmission in the process of memory acquisition and consolidation, while no consistent report is available to address the adaptation of hippocampal GABAergic transmission and its contribution to memory deficiency in the setting of Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF) is a key molecule that regulates GABAergic transmission. In the brain, mature BDNF is generated from the proteolytic cleavage of proBDNF, while BDNF and proBDNF have differential effects on central GABAergic transmission. First, the present study reports a remarkable increase of proBDNF/BNDF ratio in the hippocampal CA1 area in rodent models of AD, indicating a potential impaired process of BDNF maturation from proBDNF cleavage. We report a suppressed hippocampal GABAergic strength, potentially resulting from the reduced expression of anion chloride co-transporter KCC2 and subsequent positive shift of GABAergic Cl-equilibrium potential (ECl-), which is attenuated by microinjection of BDNF with proBDNF inhibitor TAT-Pep5. We also show that normalization of proBDNF/BDNF signaling or GABAergic ECl-by intracerebroventricular (i.c.v.) administration of bumetanide remarkably improves the cognitive performance in Morris water maze test and fear conditioning test in rodent models of AD. These results demonstrate a critical role of hippocampal proBDNF/BDNF in regulating GABAergic transmission and contributing to memory dysfunction in rodent models of AD.

Amyloid Fibril-Induced Astrocytic Glutamate Transporter Disruption Contributes to Complement C1q-Mediated Microglial Pruning of Glutamatergic Synapses.

The complement C1q plays a critical role in microglial phagocytosis of glutamatergic synapses and in the pathogenesis of neuroinflammation in Alzheimer's disease (AD). We recently reported that upregulation of metabotropic glutamate receptor signaling is associated with increased synaptic C1q production and subsequent microglial phagocytosis of synapses in the rodent models of AD. Here, we explored the role of astrocytic glutamate transporter in the synaptic C1q production and microglial phagocytosis of hippocampal glutamatergic synapses in a rat model of AD. Activation of astrocyte and reduction glutamate transporter 1 (GLT1) were noted after bilateral microinjection of amyloid-beta (Aß1-40) fibrils into the hippocampal CA1 area of rats. Ceftriaxone is a ß-lactam antibiotic that upregulates GLT1 expression. Bilateral microinjection of ceftriaxone recovered GLT1 expression, decreased synaptic C1q production, suppressed microglial phagocytosis of glutamatergic synapses in the hippocampal CA1, and attenuated synaptic and cognitive deficits in rats microinjected with Aß1-40. In contrast, artificial suppression of GLT1 activity by DL-threo-beta-benzyloxyaspartate (DL-TBOA) in naïve rats induced synaptic C1q expression and microglial phagocytosis of glutamatergic synapses in the hippocampal CA1 area, resulting in synaptic and cognitive dysfunction. These findings demonstrated that impairment of astrocytic glutamate transporter plays a role in the pathogenesis of AD.

Activation of mGluR1 Mediates C1q-Dependent Microglial Phagocytosis of Glutamatergic Synapses in Alzheimer's Rodent Models.

Microglia and complements appear to be involved in the synaptic and cognitive deficits in Alzheimer's disease (AD), though the mechanisms remain elusive. In this study, utilizing two types of rodent model of AD, we reported increased complement C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses, which led to synaptic and cognitive deficits. We also found increased activity of the metabotropic glutamate receptor 1 (mGluR1) in hippocampal CA1 in the modeled rodents. Artificial activation of mGluR1 signaling promoted dephosphorylation of fragile X mental retardation protein (FMRP) and facilitated the local translation machinery of synaptic C1q mRNA, thus mimicking the C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses and synaptic and cognitive deficiency in the modeled rodents. However, suppression of mGluR1 signaling inhibited the dephosphorylation of FMRP and repressed the local translation of synaptic C1q mRNA, which consequently alleviated microglial phagocytosis of synapses and restored the synaptic and cognitive function in the rodent models. These findings illustrate a novel molecular mechanism underlying C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses in AD.

Cannabinoid Type 2 Receptor System Modulates Paclitaxel-Induced Microglial Dysregulation and Central Sensitization in Rats.

Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl) piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα), transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K+-Cl- cotransporter, and induced mechanical allodynia in rats. All of the aforementioned molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced molecular and behavioral changes in rats. Perspective: This study provides evidence that paclitaxel induced microglia dysregulation and epigenetically upregulated the microglial expression of BDNF, which led to sensitization of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated these pathological processes. MDA7 represents an innovative therapeutic approach for treatment of chemotherapy-induced neuropathy.

An overview of the cannabinoid type 2 receptor system and its therapeutic potential.

PURPOSE OF REVIEW: This narrative review summarizes recent insights into the role of the cannabinoid type 2 (CB2) receptor as potential therapeutic target in neuropathic pain and neurodegenerative conditions. RECENT FINDINGS: The cannabinoid system continues to receive attention as a therapeutic target. The CB2 receptor is primarily expressed on glial cells only when there is active inflammation and appears to be devoid of undesired psychotropic effects or addiction liability. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases with limited or no currently approved therapies, such as neuropathic pain and neurodegenerative conditions such as Alzheimer's disease. SUMMARY: The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.

Amyloid fibrils induce dysfunction of hippocampal glutamatergic silent synapses.

Silent glutamatergic synapses lacking functional AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors exist in several brain regions including the hippocampus. Their involvement in the dysfunction of hippocampal glutamatergic transmission in the setting of Alzheimer's disease (AD) is unknown. This study demonstrated a decrease in the percentage of silent synapses in rats microinjected with amyloid fibrils (Aß1-40 ) into the hippocampal CA1. Also, pairing low-frequency electric stimuli failed to induce activation of the hippocampal silent synapses in the modeled rats. Immunoblotting studies revealed a decreased expression of GluR1 subunits in the hippocampal CA1 synaptosomal preparation, indicating a potential reduction in the GluR1 subunits anchoring in postsynaptic density in the modeled rats. We also noted a decreased expression of phosphorylated cofilin, which regulates the function of actin cytoskeleton and receptor trafficking, and reduced expression of the scaffolding protein PSD95 in the hippocampal CA1 synaptosome in rats injected with Aß1-40 . Taken together, this study illustrates dysfunction of hippocampal silent synapse in the rodent model of AD, which might result from the impairments of actin cytoskeleton and postsynaptic scaffolding proteins induced by amyloid fibrils.

Activation of CB2 receptor system restores cognitive capacity and hippocampal Sox2 expression in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuroinflammation, extensive deposits of amyloid-ß aggregates, and loss of memory and cognitive abilities. The brains of patients with AD show increased expression of cannabinoid receptor type 2 (CB2) receptors and glial markers. CB2 receptors act as a negative feedback regulator; when activated by a CB2 agonist, they can help limit the extent of the neuroinflammatory response and the subsequent development of neuronal damage in the central nervous system. In a double transgenic APP/PS1 mice model of AD, we evaluated the effect of MDA7, a CB2 agonist, on several neuropathological conditions of AD including amyloid deposition, inflammatory reaction, Sox2 (sex-determining region Y-box 2) expression, and spatial memory. Activation of microglia CB2 receptors by MDA7 suppressed neuroinflammation, demonstrated by decreased immunosignal of Iba1 in the hippocampal CA1 and dentate gyrus (DG) areas, promoted clearance of amyloid plaques in the DG area, restored Sox2 expression, and promoted recovery of the neuronal synaptic plasticity in hippocampal CA1. In addition, treatment with MDA7 improved the behavioral performance in the Morris water maze in APP/PS1mice. Collectively, these findings suggest that MDA7 has a potential therapeutic effect in the setting of AD.

Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post-ischemic pain model of complex regional pain syndrome type I in rats.

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

Epigenetic Manipulation of Brain-derived Neurotrophic Factor Improves Memory Deficiency Induced by Neonatal Anesthesia in Rats.

BACKGROUND: Although neonatal exposure to anesthetic drugs is associated with memory deficiency in rodent models and possibly in pediatric patients, the underlying mechanisms remain elusive. The authors tested their hypothesis that exposure of the developing brain to anesthesia triggers epigenetic modification, involving the enhanced interaction among transcription factors (histone deacetylase 2, methyl-cytosine-phosphate-guanine-binding protein 2, and DNA methyltransferase 1) in Bdnf promoter region(s) that inhibit brain-derived neurotrophic factor (BDNF) expression, resulting in insufficient drive for local translation of synaptic mRNAs. The authors further hypothesized that noninvasive environmental enrichment (EE) will attenuate anesthesia-induced epigenetic inhibition of BDNF signaling and memory loss in rodent models. METHODS: Seven days after birth (P7), neonatal rats were randomly assigned to receive either isoflurane anesthesia for 6 h or sham anesthesia. On P21, pups were weaned, and animals were randomly assigned to EE or a standard cage environment (no EE). Behavioral, molecular, and electrophysiological studies were performed on rats on P65. RESULTS: The authors found a substantial reduction of hippocampal BDNF (n = 6 to 7) resulting from the transcriptional factors-mediated epigenetic modification in the promoter region of Bdnf exon IV in rats exposed postnatally to anesthetic drugs. This BDNF reduction led to the insufficient drive for the synthesis of synaptic proteins (n = 6 to 8), thus contributing to the hippocampal synaptic (n = 8 to 11) and cognitive dysfunction (n = 10) induced by neonatal anesthesia. These effects were mitigated by the exposure to an enriched environment. CONCLUSIONS: The findings of this study elucidated the epigenetic mechanism underlying memory deficiency induced by neonatal anesthesia and propose EE as a potential therapeutic approach.

Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency.

Amyloid-induced microglial activation and neuroinflammation impair central synapses and memory function, although the mechanism remains unclear. Neuroligin 1 (NLGN1), a postsynaptic protein found in central excitatory synapses, governs excitatory synaptic efficacy and plasticity in the brain. Here we found, in rodents, that amyloid fibril-induced neuroinflammation enhanced the interaction between histone deacetylase 2 and methyl-CpG-binding protein 2, leading to suppressed histone H3 acetylation and enhanced cytosine methylation in the Nlgn1 promoter region and decreased NLGN1 expression, underlying amyloid-induced memory deficiency. Manipulation of microglia-associated neuroinflammation modulated the epigenetic modification of the Nlgn1 promoter, hippocampal glutamatergic transmission and memory function. These findings link neuroinflammation, synaptic efficacy and memory, thus providing insight into the pathogenesis of amyloid-associated diseases.

Suppression of central chemokine fractalkine receptor signaling alleviates amyloid-induced memory deficiency.

The abnormal accumulation of amyloid fibrils in the brain is pathognomonic of Alzheimer's disease. Amyloid fibrils induce significant neuroinflammation characterized by the activation of microglia and impairment of synaptic plasticity in the brain that eventually leads to cognitive decline. Chemokine fractalkine receptor (CX3CR1) is primarily located in the microglia in the brain and its role in the amyloid fibril-induced neuroinflammation and memory deficiency remains debated. We found that bilateral microinjection of amyloid beta (Aß)1-40 fibrils into the hippocampal CA1 area of rats resulted in significant upregulation of CX3CR1 messenger RNA (mRNA) and protein expression (via increasing histone H3 acetylation in the Cx3cr1 promoter region), synaptic dysfunction, and cognitive impairment, compared with the control group. Suppressing CX3CR1 signaling with CX3CR1 small interfering RNA in rats injected with Aß1-40 fibrils blunted Aß1-40-induced CX3CR1 upregulation, microglial activation, interleukin-1ß expression, restored basal glutamatergic strength and electric stimuli-induced long-term potentiation, and cognitive capacities. These findings suggest that activation of CX3CR1 plays an important role in the neuroinflammatory response and Aß-induced neuroinflammation and neurotoxicity.

Activation of the CB2 receptor system reverses amyloid-induced memory deficiency.

Cannabinoid type 2 (CB(2)) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer's disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7)-a novel selective CB(2) agonist that lacks psychoactivity-on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-ß (Aß)(1-40) fibrils into the hippocampal CA1 area of rats. In rats injected with Aß(1-40) fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1ß, (3) decreased the upsurge of CB(2) receptors, (4) promoted Aß clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer's disease.

Upregulation of nerve growth factor in central amygdala increases sensitivity to opioid reward.

The rewarding properties of opioids are essential driving force for compulsive drug-seeking and drug-taking behaviors in the development of opioid-mediated drug addiction. Prior drug use enhances sensitivity to the rewarding effects of subsequently used drugs, increasing vulnerability to relapse. The molecular mechanisms underlying this reward sensitization are still unclear. We report here that morphine that induced reward sensitization, as demonstrated by reinstatement of the behavior of conditioned place preference (CPP) with sub-threshold priming morphine, epigenetically upregulated the output activity of Ngf encoding the nerve growth factor (NGF) by increasing histone H4 acetylation in the rat central nucleus of the amygdala (CeA). NGF locally infused into the CeA mimicked the morphine effect in inducing new functional delta-opioid receptor (DOR) that was required for the reward sensitization, and morphine-induced reward sensitization was inhibited by blocking NGF receptor signaling in the CeA. Histone deacetylase inhibitors that increased the acetylation level at the Ngf promoter and NGF expression in the CeA also induced reward sensitization in a CeA NGF signaling- and DOR-dependent manner. Furthermore, CeA-applied NGF substituted prior morphine to induce reward sensitization in naive rats and also substituted priming morphine to reinstate the CPP induced by prior morphine. Thus, epigenetic upregulation of NGF activity in the CeA may promote the behavior of opioid reward and increase the sensitivity to the rewarding effect of subsequent opioids, a potentially important mechanism in drug addiction.

Fundamental concepts of epigenetics for consideration in anesthesiology.

PURPOSE OF REVIEW: Epigenetics dictate how the genetic blueprint is ultimately expressed and, therefore, is fundamental to our understanding of disease etiology and cellular responses and consequences to exposure of stimuli, such as anesthetics and perioperative stress. The goal of this review is to provide a concise overview of the fundamental concepts in epigenetics and discuss how epigenetics may be incorporated into research studies in anesthesiology. RECENT FINDINGS: Chemical modifications of DNA and core histone proteins are epigenetic marks that constitute the functional genome and are key to generating diverse cellular phenotypes from the same genotype. These modifications and the cellular machineries that regulate them are essential for maintaining tissue-specific and timing-specific expression profiles for normal functioning and can be altered in disease contexts, thus providing the molecular basis for the abnormalities. Similar to determining cellular identity within a person, epigenetic differences between individuals, including monozygotic twins, can account for disparate phenotypes in the absence of genetic variation in the genes of interest. Furthermore, epigenetic modifications are dynamic but heritable and, thus, are fitting for reinforcing adaptive phenotypes in response to external stimuli. SUMMARY: Epigenetic mechanisms underlie many human pathological conditions and impact clinical management in a variety of contexts. Although epigenetic research related to anesthesiology is sparse at the present, the full understanding of the mechanism of action of analgesics, interindividual variations in responses to anesthetics and consequences of exposure to anesthetic drugs will likely require the evaluation and integration of epigenetic information into current research paradigms.

Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system.

BACKGROUND: Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB(2)) receptors are expressed in the microglia in neurodegenerative disease models. METHODS: To explore the potential of CB(2) agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB(2)-selective agonist, namely, MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB(2)(+/+) and CB(2)(-/-) mice. We hypothesized that the CB(2) receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways. RESULTS: We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB(2)(-/-) mice and was blocked by CB(2) antagonists, suggesting that MDA7's action directly involves CB(2) receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced toll-like receptor and CB(2) expression in the lumbar spinal cord, reduced levels of extracellular signal-regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models. CONCLUSIONS: Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae.

Epigenetic suppression of GAD65 expression mediates persistent pain.

Chronic pain is a common neurological disease involving lasting, multifaceted maladaptations ranging from gene modulation to synaptic dysfunction and emotional disorders. Sustained pathological stimuli in many diseases alter the output activities of certain genes through epigenetic modifications, but it is unclear how epigenetic mechanisms operate in the development of chronic pain. We show here that in the rat brainstem nucleus raphe magnus, which is important for central mechanisms of chronic pain, persistent inflammatory and neuropathic pain epigenetically suppresses Gad2 (encoding glutamic acid decarboxylase 65 (GAD65)) transcription through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired γ-aminobutyric acid (GABA) synaptic inhibition. Gad2 knockout mice showed sensitized pain behavior and impaired GABA synaptic function in their brainstem neurons. In wild-type but not Gad2 knockout mice, HDAC inhibitors strongly increased GAD65 activity, restored GABA synaptic function and relieved sensitized pain behavior. These findings suggest GAD65 and HDACs as potential therapeutic targets in an epigenetic approach to the treatment of chronic pain.