ST2-104 attenuates neuronal injuries in A beta(25-35)-induced AD rats by inhibiting CRMP2-NMDAR2B signaling pathways

Collapsin response mediator protein 2 (CRMP2), traditionally regarded as an axon/dendrite growth and guidance protein, plays an important role in the regulation of both post-and pre-synaptic Ca2+ channels, such as N-methyl-d-aspartate receptors (NMDARs). The Ca2+ channel-binding domain 3 (CBD3) peptide derived from CRMP2 has recently emerged as a Ca2+ channel blocker, suppressing neuropathic pain in a spared nerve injury (SNI) model when linked to the transduction domain of HIV TAT protein and reduced neuronal death in a middle cerebral artery occlusion model and a traumatic brain injury (TBI) model. The present study aimed to examine the neuroprotective effects and biochemical mechanisms of ST2-104 (a non-arginine-conjugated CBD3 peptide) in an A beta(25-35)-induced Alzheimer's disease (AD) rat model. This study demonstrated that CRMP2 and NMDARs subunit NMDAR2B form a direct biochemical complex, which regulates NMDAR activity in a rat model. ST2-104 peptide given via tail vein injections significantly reduced spatial learning and memory impairment. ST2-104 relieved neuronal injuries by suppressing expression of NMDAR2B and p-CRMP2 and increasing expression of CRMP2 in the hippocampus. Remarkably, ST2-104 attenuated levels of intracellular Ca2+ by disrupting the interaction between p-CRMP2 and NMDAR2B. Taken together, these findings support ST2-104 as a novel neuroprotective agent, potentially representing a novel direction for a therapeutic targeting channel in AD.National Natural Science Foundation of China [81571231]; Health and Family Planning Commission of Jilin Province [2015Z043]; Department of Education Foundation of Jilin Province [JJKH20190102KJ]; Department Science and Technology Foundation of Jilin Province [20190701058GH]; Talent Development Fund of Jilin ProvinceOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Differential expression of Cdk5-phosphorylated CRMP2 following a spared nerve injury

Effective treatment of high-impact pain patients is one of the major stated goals of the National Pain Strategy in the United States. Identification of new targets and mechanisms underlying neuropathic pain will be critical in developing new target-specific medications for better neuropathic pain management. We recently discovered that peripheral nerve injury-induced upregulation of an axonal guidance phosphoprotein collapsin response mediator protein 2 (CRMP2) and the N-type voltage-gated calcium (CaV2.2) as well as the NaV1.7 voltage-gated sodium channel, correlates with the development of neuropathic pain. In our previous studies, we found that interfering with the phosphorylation status of CRMP2 is sufficient to confer protection from chronic pain. Here we examined the expression of CRMP2 and CRMP2 phosphorylated by cyclin-dependent kinase 5 (Cdk5, on serine residue 522 (S522)) in sciatic nerve, nerve terminals of the glabrous skin, and in select subpopulations of DRG neurons in the SNI model of neuropathic pain. By enhancing our understanding of the phosphoregulatory status of CRMP2 within DRG subpopulations, we may be in a better position to design novel pharmacological interventions for chronic pain.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

1-O-Acetylgeopyxin A, a derivative of a fungal metabolite, blocks tetrodotoxin-sensitive voltage-gated sodium, calcium channels and neuronal excitability which correlates with inhibition of neuropathic pain

Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Dissecting the role of the CRMP2–neurofibromin complex on pain behaviors

Neurofibromatosis type 1 (NF1), a genetic disorder linked to inactivating mutations or a homozygous deletion of the Nf1 gene, is characterized by tumorigenesis, cognitive dysfunction, seizures, migraine, and pain. Omic studies on human NF1 tissues identified an increase in the expression of collapsin response mediator protein 2 (CRMP2), a cytosolic protein reported to regulate the trafficking and activity of presynaptic N-type voltage-gated calcium (Cav2.2) channels. Because neurofibromin, the protein product of the Nf1 gene, binds to and inhibits CRMP2, the neurofibromin-CRMP2 signaling cascade will likely affect Ca channel activity and regulate nociceptive neurotransmission and in vivo responses to noxious stimulation. Here, we investigated the function of neurofibromin-CRMP2 interaction on Cav2.2. Mapping of >275 peptides between neurofibromin and CRMP2 identified a 15-amino acid CRMP2-derived peptide that, when fused to the tat transduction domain of HIV-1, inhibited Ca influx in dorsal root ganglion neurons. This peptide mimics the negative regulation of CRMP2 activity by neurofibromin. Neurons treated with tat-CRMP2/neurofibromin regulating peptide 1 (t-CNRP1) exhibited a decreased Cav2.2 membrane localization, and uncoupling of neurofibromin-CRMP2 and CRMP2-Cav2.2 interactions. Proteomic analysis of a nanodisc-solubilized membrane protein library identified syntaxin 1A as a novel CRMP2-binding protein whose interaction with CRMP2 was strengthened in neurofibromin-depleted cells and reduced by t-CNRP1. Stimulus-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices was inhibited by t-CNRP1. Intrathecal administration of t-CNRP1 was antinociceptive in experimental models of inflammatory, postsurgical, and neuropathic pain. Our results demonstrate the utility of t-CNRP1 to inhibit CRMP2 protein-protein interactions for the potential treatment of pain

Yellowfin Tuna (Thunnusalbacares) Fishing Ground Forecasting Model Based On Bayes Classifier In The South China Sea

Using the yellowfin tuna (Thunnusalbacares,YFT)longline fishing catch data in the open South China Sea (SCS) provided by WCPFC, the optimum interpolation sea surface temperature (OISST) from CPC/NOAA and multi-satellites altimetric monthly averaged product sea surface height (SSH) released by CNES, eight alternative options based on Bayes classifier were made in this paper according to different strategies on the choice of environment factors and the levels of fishing zones to classify the YFT fishing ground in the open SCS. The classification results were compared with the actual ones for validation and analyzed to know how different plans impact on classification results and precision. The results of validation showed that the precision of the eight options were 71.4%, 75%, 70.8%, 74.4%, 66.7%, 68.5%, 57.7% and 63.7% in sequence, the first to sixth among them above 65% would meet the practical application needs basically. The alternatives which use SST and SSH simultaneously as the environmental factors have higher precision than which only use single SST environmental factor, and the consideration of adding SSH can improve the model precision to a certain extent. The options which use CPUE’s mean ± standard deviation as threshold have higher precision than which use CPUE’s 33.3%-quantile and 66.7%-quantile as the threshol

A light-gated potassium channel for sustained neuronal inhibition

Currently available inhibitory optogenetic tools provide short and transient silencing of neurons, but they cannot provide long-lasting inhibition because of the requirement for high light intensities. Here we present an optimized blue-light-sensitive synthetic potassium channel, BLINK2, which showed good expression in neurons in three species. The channel is activated by illumination with low doses of blue light, and in our experiments it remained active over (tens of) minutes in the dark after the illumination was stopped. This activation caused long periods of inhibition of neuronal firing in ex vivo recordings of mouse neurons and impaired motor neuron response in zebrafish in vivo. As a proof-of-concept application, we demonstrated that in a freely moving rat model of neuropathic pain, the activation of a small number of BLINK2 channels caused a long-lasting (>30 min) reduction in pain sensation.status: publishe