Abstract
In neuropathic pain (NP), the atrophy of hippocampus contributes to the comorbidity between pain, depression and the cognitive deficits. However, the exact mechanism underling the comorbidity, the effective control of the degenerations in hippocampus and the remission of the accompanied depressive symptoms are still lacking. Wu-Tou decoction (WTD) has been prescribed for inflammatory pain for thousands of years. In this study, we manifested the effects of WTD on the pain, depression and anxiety co-curative symptoms of NP. Moreover, we reported that WTD rescued the mal-regulated BDNF and TNF-α in hippocampal CA3 alone, which is proven contributing to the pain and induced psychiatric symptoms. Finally, analysis of biochemistry, morphology and electrophysiology exhibited the potential mechanism of WTD in CA3. We found that, in the late stage of SNL condition, WTD mediated the rescue of the down-regulated glutamate as well as its pre-synaptic vesicular glutamate transporters (VGLuT1) and the post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in CA3. In sum, the targeted mediation of glutamatergic system in CA3 suggest that WTD may be responsible for the remission of the hypo-functioned CA3 glutamatergic neurons and further contribute to the co-curative effects of WTD.
Highlights
Excessive activation of peripheral neurons, more important to the resistance and the complication of the disease[14]
For Pregabalin (PGB), increased threshold were manifested during the whole disease process exposure to the drug administration after 1 hour; whereas, the significant increases detected 24 hrs after PGB administration disappeared after D9, which indicates that the effectiveness of PGB is hampered by the long-term administration
Compared to pregabalin, the effectiveness of Wu-Tou decoction (WTD)-H is more evident after the long-term administration. (Fig. 1A)
Summary
Excessive activation of peripheral neurons, more important to the resistance and the complication of the disease[14]. To clarify the pharmacological mechanism underling the long-term administration of WTD, we construed the spinal cord ligation (SNL) mice model and confirmed the WTD mediated remission of NP symptoms and the regulation of BDNF and TNF-α in CA3. On this basis, we hypothesized that: 1: The long term deprivation of BDNF and up-regulation of TNF-α in CA3 underline the co-comorbidity of the cognitive deficits, depressive, anxiety as well as the nociceptive behaviors; 2: The co-curative effects of WTD is dependent on CA3; 3. The quantifications of glutamate and its pre/post-synaptic receptors at the level of protein expression, the co-localization of BDNF and glutamate receptors by fluorescent double staining and the mEPSC analysis of hippocampal CA3 pyramidal neurons were further performed
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