Journal of molecular neuroscience : MN
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Increasing evidence underscores the strong, rapid, and sustained antidepressant properties of ketamine with a good tolerability profile in patients with depression; however, the underlying mechanisms are not fully elucidated. Neuregulin 1 (NRG1) is a bipolar disorder susceptibility gene and a biomarker of major depressive disorder, which regulates pyramidal neuron activity via ErbB4 in parvalbumin interneurons. Moreover, NRG1-ErbB4 signaling is reported to play a key role in the modulation of synaptic plasticity through regulating the neurotransmission. ⋯ The results showed that ketamine reduced the immobility time and latency to feed of rats receiving the FST, downregulated the levels of NRG1, phosphorylated ErbB4 (p-ErbB4), parvalbumin, 67-kDA isoform of glutamic acid decarboxylase (GAD67), gamma-aminobutyric acid (GABA), and upregulated the levels of glutamate in the rat prefrontal cortex and hippocampus. Pretreatment with NRG1 abolished both ketamine's antidepressant effects and ketamine-induced reduction in p-ErbB4, parvalbumin, GAD67, and GABA levels and increase in glutamate levels. These results suggest that the downregulation of NRG1-ErbB4 signaling in parvalbumin interneurons in the rat brain may be a mechanism underlying ketamine's antidepressant properties.
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Treating neuropathic pain is a major clinical challenge, and several key molecules associated with nociception have been suggested as potential targets for novel analgesics. Many studies have reported the anti-nociceptive effects of glial cell-derived neurotrophic factor (GDNF), but the underlying mechanism remains largely unknown. The present study was performed to assess the effects of GDNF in a mouse model of chronic constriction injury (CCI)-induced neuropathic pain. ⋯ Together, these data demonstrated that E-cadherin-associated p120ctn was upregulated by GDNF and that this upregulation was inhibited by pre-treatment with DECMA-1. Moreover, DECMA-1 significantly inhibited the effect of GDNF on thermal hyperalgesia. These data suggest that GDNF might have a therapeutic potential for the treatment of CCI-induced neuropathic pain and that the E-cadherin/p120ctn might play a role in GDNF-induced attenuation of thermal hyperalgesia.