Neuropeptides最新文献

Botulinum toxin type A (BoNT/A) induces direct analgesic effects in neuropathic pain by inhibiting the release of substance P, calcitonin gene-related peptide (CGRP) and glutamate. Vesicular nucleotide transporter (VNUT) was responsible for the storage and release of ATP in vivo, and one of the mechanisms underlying neuropathic pain is VNUT-dependent release of extracellular ATP from dorsal horn neurons. However, the analgesic effect of BoNT/A by affecting the expression of VNUT remained largely unknown. Thus, in this study, we aimed to elucidate the antinociceptive potency and analgesic mechanism of BoNT/A in chronic constriction injury of the sciatic nerve (CCI) induced neuropathic pain. Our results showed that a single intrathecal injection of 0.1 U BoNT/A seven days after CCI surgery produced significant analgesic activity and decreased the expression of VNUT in the spinal cord of CCI rats. Similarly, BoNT/A inhibited the CCI-induced increase in ATP content in the rat spinal cord. Overexpression of VNUT in the spinal cord of CCI-induced rats markedly reversed the antinociceptive effect of BoNT/A. Furthermore, 33 U/mL BoNT/A dramatically reduced the expression of VNUT in pheochromocytoma (PC12) cells but overexpressing SNAP-25 increased VNUT expression in PC12 cells. Our current study is the first to demonstrate that BoNT/A is involved in neuropathic pain by regulating the expression of VNUT in the spinal cord in rats.

Patients with a spinal cord injury (SCI) usually suffer lifelong disability as a result. Considering this, SCI treatment and pathology study are urgently needed. Metformin, a widely used hypoglycemic drug, has been indicated for its important role in central nervous system diseases. This study aimed to investigate the potential effect of metformin on remyelination after SCI. In the present study, we established a cervical contusion SCI model and metformin treatment was applied after SCI. Biomechanical parameters and behavioral assessment were used to evaluate the severity of injury and the improvement of functional recovery after SCI, respectively. The immunofluorescence and western blot were performed at the terminal time point. Our results showed that treating with metformin after SCI improved functional recovery by reducing the white matter loss and promoting Schwann cell remyelination, and the Nrg1/ErbB signaling pathway may be involved in promoting remyelination mediated by oligodendrocytes and Schwann cells. In addition, the area of spared tissues was significantly increased in the metformin group. However, metformin had no significant effects on the glial scar and inflammation after SCI. In summary, these findings indicated that the role of metformin in Schwann cell remyelination after SCI was probably related to the regulation of the Nrg1/ErbB pathway. It is, therefore, possible to suggest that metformin may be a potential therapy for SCI.

Prolactin-releasing peptide (PrRP) has been investigated as a potential therapeutic for diabetes by the effect of food intake reduction, increasing leptin signaling, and insulin tolerance. Recent studies focused on its synaptogenesis and protective effects against neurodegeneration. Whereas 1,2-diacetylbenzene (DAB), a common metabolite of a neurotoxicant 1,2-diethyl benzene, causes memory impairment and neurotoxicity partly through the inflammatory process. Our present study assessed the effect of PrRP in microglia and its action in balancing the inflammation to protect against DAB. We observed that PrRP modulated NADPH oxidase - regulated NLRP3 inflammasome and PRL signaling pathways differently between physical and toxic conditions in microglia.

Arginine vasopressin (AVP) plays a hypothermic regulatory role in thermoregulation and is an important endogenous mediator in this mechanism. In the preoptic area (POA), AVP increases the spontaneous firing and thermosensitivity of warm-sensitive neurons and decreases those of cold-sensitive and temperature-insensitive neurons. Because POA neurons play a crucial role in precise thermoregulatory responses, these findings indicate that there is an association between the hypothermia and changes in the firing activity of AVP-induced POA neurons. However, the electrophysiological mechanisms by which AVP controls this firing activity remain unclear. Therefore, in the present study, using in vitro hypothalamic brain slices and whole-cell recordings, we elucidated the membrane potential responses of temperature-sensitive and –insensitive POA neurons to identify the applications of AVP or V_1a vasopressin receptor antagonists. By monitoring changes in the resting potential and membrane potential thermosensitivity of the neurons before and during experimental perfusion, we observed that AVP increased the changes in the resting potential of 50% of temperature-insensitive neurons but reduced them in others. These changes are because AVP enhances the membrane potential thermosensitivity of nearly 50% of the temperature-insensitive neurons. On the other hand, AVP changes both the resting potential and membrane potential thermosensitivity of temperature-sensitive neurons, with no differences between the warm- and cold-sensitive neurons. Before and during AVP or V_1a vasopressin receptor antagonist perfusion, no correlation was observed between changes in the thermosensitivity and membrane potential of all neurons. Furthermore, no correlation was observed between the thermosensitivity and membrane potential thermosensitivity of the neurons during experimental perfusion. In the present study, we found that AVP induction did not result in any changes in resting potential, which is unique to temperature-sensitive neurons. The study results suggest that AVP-induced changes in the firing activity and firing rate thermosensitivity of POA neurons are not controlled by resting potentials.

Objective

Chinese herbal formulas show considerable therapeutic benefits in dementia. This study specifically explored the protective action of Zishen Huoxue recipe on the neurovascular unit (NVU) of rats with vascular dementia (VD).

Methods

VD rat models were established by permanent bilateral common carotid artery occlusion and treated with Zishen Huoxue recipe. In vitro glucose‑oxygen deprivation (OGD)-injured NVU models were established and treated with miR-124-3p agomir or rat medicated serum. The neurological damage, histopathological changes, and neuronal injury in the rat hippocampus were assessed using Morris water maze test and histological stainings. Expression of miR-124-3p was determined using RT-qPCR. The blood-brain barrier/NVU injury, cell pyroptosis, NLRP3 inflammasome activation, and release of inflammatory factors were analyzed mainly by immunofluorescence analysis, TUNEL staining, Western blot, and ELISA. QS-21 (an NLRP3 activator) was used to verify the role of miR-124-3p/NLRP3.

Results

Zishen Huoxue recipe ameliorated the learning/memory deficits, neuronal injury, NVU insults, cell pyroptosis, activation of NLRP3 inflammasome, and extensive secretion of lactate dehydrogenase/IL-1β/IL-18 in VD rats. miR-124-3p was downregulated in VD rats but upregulated after treatment of this recipe. miR-124-3p overexpression ameliorated NVU insults, reduced cell pyroptosis, lowered NLRP3 inflammasome activation, and suppressed inflammatory responses in OGD-injured NVU models. NLRP3 inflammasome activation partly counteracted the amelioration effect of miR-124-3p on pyroptosis. Zishen Huoxue recipe could upregulate miR-124-3p to suppress pyroptosis and protect NVU function.

Conclusion

Zishen Huoxue recipe can upregulate miR-124-3p expression to repress the inflammatory cascade-evoked pyroptosis, thereby protecting against neuronal injury in the NVU of VD rats.

Background

Trigeminal neuralgia is a common chronic maxillofacial neuropathic pain disorder, and voltage-gated sodium channels (VSGCs) are likely involved in its pathology. Prior studies report that pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide highly expressed in the trigeminal ganglion, may contribute to dorsal root ganglion neuron excitability by modulating the Nav1.7.

Objective

We investigated whether PACAP can regulate Nav1.7 through the mitogen-activated protein kinase/ERK kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway in the trigeminal ganglion after chronic constriction injury of the infraorbital nerve (ION-CCI) in rats.

Study design

Sprague-Dawley rats underwent ION-CCI, followed by intrathecal injection of PACAP 6–38 (PAC1 receptor antagonist) and PD98059 (MEK/ERK antagonist). Quantitative real-time PCR and western blot were used to quantify ATF3, PACAP, ERK, p-ERK, and Nav1.7 expression.

Results

The mechanical pain threshold decreased from day 3 to day 21 after ION-CCI and reached the lowest testing value by day 14; however, it increased after PACAP 6–38 and PD98059 injections. Additionally, ION-CCI surgery increased ATF3, PACAP, and p-ERK expression in the rat trigeminal ganglion and decreased Nav1.7 and PAC1 receptor expression; however, there was no difference in ERK expression. PACAP 6–38 injection significantly decreased PACAP, p-ERK, and Nav1.7 expression and increased the PAC1 receptor expression, with no change in ERK expression. Moreover, PD98059 injection decreased PACAP, p-ERK, and Nav1.7 expression and increased the expression of PAC1 receptor.

Conclusion

After ION-CCI, PACAP in the rat trigeminal ganglion can modulate Nav1.7 through the MEK/ERK pathway via the PAC1 receptor. Further, PACAP inhibition alleviates allodynia in ION-CCI rats.

Multiple factors regulate the regeneration of craniofacial bone defects. The nervous system is recognized as one of the critical regulators of bone mass, thereby suggesting a role for neuronal pathways in bone regeneration. However, in the context of craniofacial bone regeneration, little is known about the interplay between the nervous system and craniofacial bone. Sensory and sympathetic nerves interact with the bone through their neuropeptides, neurotransmitters, proteins, peptides, and amino acid derivates. The neuron-derived factors, such as semaphorin 3A (SEMA3A), substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP), possess a remarkable role in craniofacial regeneration. This review summarizes the roles of these factors and recently published factors such as secretoneurin (SN) and spexin (SPX) in the osteoblast and osteoclast differentiation, bone metabolism, growth, remodeling and discusses the novel application of nerve-based craniofacial bone regeneration. Moreover, the review will facilitate understanding the mechanism of action and provide potential treatment direction for the craniofacial bone defect.

Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons display altered spontaneous firing activity in Parkinson's disease. The firing rate of nigral dopaminergic neurons decreases long before complete neuronal death and the appearance of parkinsonian symptoms. A mild stimulation could rescue dopaminergic neurons from death and in turn play neuroprotective effects. Several neuropeptides, including cholecystokinin (CCK), ghrelin, neurotensin, orexin, tachykinins and apelin, within the substantia nigra pars compacta play important roles in the modulation of spontaneous firing activity of dopaminergic neurons and therefore involve motor control and motor disorders. Here, we review neuropeptide-induced modulation of the firing properties of nigral dopaminergic neurons. This review may provide a background to guide further investigations into the involvement of neuropeptides in movement control by modulating firing activity of nigral dopaminergic neurons in Parkinson's disease.

The opioid growth factor (OGF) is an endogenous peptide that binds to the nuclear-associated receptor (OGFr), and plays a significant role in the proliferation of developing, renewing, and healing tissues. The receptor is widely expressed in a variety of organs, however its distribution in the brain remains unknown. In this study, we investigated the distribution of OGFr in different brain regions of male heterozygous (-/+ Lepr ^db/J), non -diabetic mice and determined the localization of the receptor in three major brain cell types, astrocytes, microglia, and neurons. Immunofluorescence imaging revealed that the highest number of OGFr was in hippocampal CA3 subregion followed by primary motor cortex, hippocampal CA2, thalamus, caudate and hypothalamus in a descending order. Double immunostaining revealed receptor colocalization with neurons and little or no colocalization in microglia and astrocytes. The highest percentage of OGFr positive neurons was identified in the CA3. Hippocampal CA3 neurons play an important role in memory processing, learning and behavior, and motor cortex neurons are important for muscle movement. However, the significance of the OGFr receptor in these brain regions and its relevance in diseased conditions are not known. Our findings provide a basis for understanding the cellular target and interaction of the OGF- OGFr pathway in neurodegenerative diseases such as Alzheimer's, Parkinson's, and stroke where hippocampus and cortex have an important role. This foundational data may also be useful in drug discovery to modulate OGFr by opioid receptor antagonist in various CNS diseases.