Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury-Induced Mechanical Pain.

Cypin (cytosolic postsynaptic density protein 95 interactor) is the primary guanine deaminase in the central nervous system (CNS), promoting the metabolism of guanine to xanthine, an important reaction in the purine salvage pathway. Activation of the purine salvage pathway leads to the production of uric acid (UA). UA has paradoxical effects, specifically in the context of CNS injury as it confers neuroprotection, but it also promotes pain.

Cross-hemicord spinal fiber reorganization associates with cortical sensory and motor network expansion in the rat model of hemicontusion cervical spinal cord injury.

Magnetic resonance imaging plays an important role in characterizing microstructural changes and reorganization after traumatic injuries to the nervous system. In this study, we tested the feasibility of ex-vivo spinal cord diffusion tensor imaging (DTI) in combination with in vivo brain functional MRI to characterize spinal reorganization and its supraspinal association after a hemicontusion cervical spinal cord injury (SCI). DTI parameters (fractional anisotropy [FA], mean diffusion [MD]) and fiber orientation changes related to reorganization in the contused cervical spinal cord were compared to sham specimens.

Lateralized Supraspinal Functional Connectivity Correlate with Pain and Motor Dysfunction in Rat Hemicontusion Cervical Spinal Cord Injury.

Afferent nociceptive activity in the reorganizing spinal cord after SCI influences supraspinal regions to establish pain. Clinical evidence of poor motor functional recovery in SCI patients with pain, led us to hypothesize that sensory-motor integration transforms into sensory-motor interference to manifest pain. This was tested by investigating supraspinal changes in a rat model of hemicontusion cervical SCI.

Roles of neuronal toll-like receptors in neuropathic pain and central nervous system injuries and diseases.

Toll-like receptors (TLRs) are innate immune receptors that are expressed in immune cells as well as glia and neurons of the central and peripheral nervous systems. They are best known for their role in the host defense in response to pathogens and for the induction of inflammation in infectious and non-infectious diseases. In the central nervous system (CNS), TLRs modulate glial and neuronal functions as well as innate immunity and neuroinflammation under physiological or pathophysiological conditions.

Neuropathic Pain in Multiple Sclerosis and Its Animal Models: Focus on Mechanisms, Knowledge Gaps and Future Directions.

Multiple sclerosis (MS) is a multifaceted, complex and chronic neurological disease that leads to motor, sensory and cognitive deficits. MS symptoms are unpredictable and exceedingly variable. Pain is a frequent symptom of MS and manifests as nociceptive or neuropathic pain, even at early disease stages.

Supraspinal Sensorimotor and Pain-Related Reorganization after a Hemicontusion Rat Cervical Spinal Cord Injury.

Because the presence of pain impedes motor recovery in individuals with spinal cord injury (SCI), it is necessary to understand their supraspinal substrates in translational animal models. Using functional magnetic resonance imaging (fMRI) in a rat model of hemicontusion cervical SCI, supraspinal changes were mapped and correlated with sensorimotor behavioral outcomes. Female adult rats underwent sham or SCI using a 2.

Contribution of astrocytes to neuropathology of neurodegenerative diseases.

Classically, the loss of vulnerable neuronal populations in neurodegenerative diseases was considered to be the consequence of cell autonomous degeneration of neurons. However, progress in the understanding of glial function, the availability of improved animal models recapitulating the features of the human diseases, and the development of new approaches to derive glia and neurons from induced pluripotent stem cells obtained from patients, provided novel information that altered this view. Current evidence strongly supports the notion that non-cell autonomous mechanisms contribute to the demise of neurons in neurodegenerative disorders, and glia causally participate in the pathogenesis and progression of these diseases.

Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases.

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes and microglia are the principal cells that mediate innate immunity in the CNS. Pattern recognition receptors (PRRs), expressed by astrocytes and microglia, sense pathogen-derived or endogenous ligands released by damaged cells and initiate the innate immune response.

Association Between Magnetic Resonance Imaging-Based Spinal Morphometry and Sensorimotor Behavior in a Hemicontusion Model of Incomplete Cervical Spinal Cord Injury in Rats.

Structural connectivity in the reorganizing spinal cord after injury dictates functional connectivity and hence the neurological outcome. As magnetic resonance imaging (MRI)-based structural parameters are mostly accessible across spinal cord injury (SCI) patients, we studied MRI-based spinal morphological changes and their relationship to neurological outcome in the rat model of cervical SCI. Functional connectivity assessments on patients with SCI rely heavily on MRI-based approaches to investigate the complete neural axis (both spinal cord and brain).

Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury.

Background: The recruitment of immune system cells into the central nervous system (CNS) has a profound effect on the outcomes of injury and disease. Glia-derived chemoattractants, including chemokines, play a pivotal role in this process. In addition, cytokines and chemokines influence the phenotype of infiltrating immune cells.

Toll-like Receptor 4 Signaling in Neurons Enhances Calcium-Permeable α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor Currents and Drives Post-Traumatic Epileptogenesis.

Objective: Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll-like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury.

Pathological pain processing in mouse models of multiple sclerosis and spinal cord injury: contribution of plasma membrane calcium ATPase 2 (PMCA2).

Background: Neuropathic pain is often observed in individuals with multiple sclerosis (MS) and spinal cord injury (SCI) and is not adequately alleviated by current pharmacotherapies. A better understanding of underlying mechanisms could facilitate the discovery of novel targets for therapeutic interventions. We previously reported that decreased plasma membrane calcium ATPase 2 (PMCA2) expression in the dorsal horn (DH) of healthy PMCA2 mice is paralleled by increased sensitivity to evoked nociceptive pain.

Toll-like receptor 9 antagonism modulates astrocyte function and preserves proximal axons following spinal cord injury.

Increasing evidence indicates that innate immune receptors play important, yet controversial, roles in traumatic central nervous system (CNS) injury. Despite many advances, the contributions of toll-like receptors (TLRs) to spinal cord injury (SCI) remain inadequately defined. We previously reported that a toll-like receptor 9 (TLR9) antagonist, oligodeoxynucleotide 2088 (ODN 2088), administered intrathecally, improves the functional and histopathological outcomes of SCI.

A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor α signaling in mechanical pain.

Earlier studies on genetically modified mice indicated that plasma membrane calcium ATPase 2 (PMCA2), a calcium extrusion pump, plays a novel and sex-dependent role in mechanical pain responses: female, but not male, PMCA2 mice manifest increased mechanical pain compared to female PMCA2 mice. The goal of the present studies was to determine the contribution of ovarian steroids to the genotype- and sex-dependent manifestation of mechanical pain in PMCA2 versus PMCA2 mice. Ovariectomy increased mechanical pain sensitivity and 17β-estradiol (E2) replacement restored it to basal levels in PMCA2 mice, but not in PMCA2 littermates.

A toll-like receptor 9 antagonist restores below-level glial glutamate transporter expression in the dorsal horn following spinal cord injury.

Spinal cord (SC) trauma elicits pathological changes at the primary lesion and in regions distant from the injury epicenter. Therapeutic agents that target mechanisms at the injury site are likely to exert additional effects in these remote regions. We previously reported that a toll-like receptor 9 (TLR9) antagonist, oligodeoxynucleotide 2088 (ODN 2088), improves functional deficits and modulates the milieu at the epicenter in mice sustaining a mid-thoracic contusion.

Contribution of Plasma Membrane Calcium ATPases to neuronal maladaptive responses: Focus on spinal nociceptive mechanisms and neurodegeneration.

Plasma membrane calcium ATPases (PMCAs) are ion pumps that expel Ca from cells and maintain Ca homeostasis. Four isoforms and multiple splice variants play important and non-overlapping roles in cellular function and integrity and have been implicated in diseases including disorders of the central nervous system (CNS). In particular, one of these isoforms, PMCA2, is critical for spinal cord (SC) neuronal function.

Impaired sensitivity to pain stimuli in plasma membrane calcium ATPase 2 (PMCA2) heterozygous mice: a possible modality- and sex-specific role for PMCA2 in nociception.

Plasma membrane calcium ATPase 2 (PMCA2) is a calcium pump that plays important roles in neuronal function. Although it is expressed in pain-associated regions of the CNS, including in the dorsal horn (DH), its contribution to pain remains undefined. The present study assessed the role of PMCA2 in pain responsiveness and the link between PMCA2 and glutamate receptors, GABA receptors (GABARs), and glutamate transporters that have been implicated in pain processing in the DH of adult female and male PMCA2 and PMCA2 mice.

Effects of early surgical decompression on functional and histological outcomes after severe experimental thoracic spinal cord injury.

OBJECTIVE In acute traumatic brain injury, decompressive craniectomy is a common treatment that involves the removal of bone from the cranium to relieve intracranial pressure. The present study investigated whether neurological function following a severe spinal cord injury improves after utilizing either a durotomy to decompress the intradural space and/or a duraplasty to maintain proper flow of cerebrospinal fluid. METHODS Sixty-four adult female rats (n = 64) were randomly assigned to receive either a 3- or 5-level decompressive laminectomy (Groups A and B), laminectomy + durotomy (Groups C and D), or laminectomy + duraplasty with graft (Group E and F) at 24 hours following a severe thoracic contusion injury (200 kilodynes).

Delayed activation of human microglial cells by high dose ionizing radiation.

Recent studies have shown that microglia affects the fate of neural stem cells in response to ionizing radiation, which suggests a role for microglia in radiation-induced degenerative outcomes. We therefore investigated the effects of γ-irradiation on cell survival, proliferation, and activation of microglia and explored associated mechanisms. Specifically, we evaluated cellular and molecular changes associated with exposure of human microglial cells (CHME5) to low and high doses of acute cesium-137 γ rays.

Toll like receptor 9 antagonism modulates spinal cord neuronal function and survival: Direct versus astrocyte-mediated mechanisms.

Toll like receptors (TLRs) are expressed by cells of the immune system and mediate the host innate immune responses to pathogens. However, increasing evidence indicates that they are important contributors to central nervous system (CNS) function in health and in pathological conditions involving sterile inflammation. In agreement with this idea, we have previously shown that intrathecal administration of a TLR9 antagonist, cytidine-phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), ameliorates the outcomes of spinal cord injury (SCI).

Dysfunction in amygdala-prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability.

Individuals exhibiting an anxiety disorder are believed to possess an innate vulnerability that makes them susceptible to the disorder. Anxiety disorders are also associated with abnormalities in the interconnected brain regions of the amygdala and prefrontal cortex (PFC). However, the link between anxiety vulnerability and amygdala-PFC dysfunction is currently unclear.

Chronic tissue response to untethered microelectrode implants in the rat brain and spinal cord.

Objective: Microelectrodes implanted in the central nervous system (CNS) often fail in long term implants due to the immunological tissue response caused by tethering forces of the connecting wires. In addition to the tethering effect, there is a mechanical stress that occurs at the device-tissue interface simply because the microelectrode is a rigid body floating in soft tissue and it cannot reshape itself to comply with changes in the surrounding tissue. In the current study we evaluated the scar tissue formation to tetherless devices with two significantly different geometries in the rat brain and spinal cord in order to investigate the effects of device geometry.

Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury.

Concussive brain injury results in neuronal degeneration, microglial activation and enhanced excitability in the hippocampal dentate gyrus, increasing the risk for epilepsy and memory dysfunction. Endogenous molecules released during injury can activate innate immune responses including toll-like receptor 4 (TLR4). Recent studies indicate that immune mediators can modulate neuronal excitability.

Toll-like receptors in central nervous system injury and disease: a focus on the spinal cord.

Toll-like receptors (TLRs) are best known for recognizing pathogens and initiating an innate immune response to protect the host. However, they also detect tissue damage and induce sterile inflammation upon the binding of endogenous ligands released by stressed or injured cells. In addition to immune system-related cells, TLRs have been identified in central nervous system (CNS) neurons and glial subtypes including microglia, astrocytes and oligodendrocytes.

A toll-like receptor 9 antagonist improves bladder function and white matter sparing in spinal cord injury.

Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, cytidine-phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits.