Neuropathic pain is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). The conditions and the pathophysiological stat...

https://journals.sagepub.com/doi/pdf/10.1177/2058738419838383

The neuropathic pain: An overview of the current treatment and future therapeutic approaches.

In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, or neuroinflammatory reactive astrocytes. In contrast to typical astrocytes, which promote neuronal survival, support synapses, and maintain blood-brain barrier integrity, these reactive astrocytes downregulate supportive functions and begin to secrete neurotoxic factors, complement components like C3, and chemokines like CXCL10, which may facilitate recruitment of immune cells across the BBB into the CNS. The proportion of pro-inflammatory reactive astrocytes increases with age through associated microglia activation, and these pro-inflammatory reactive astrocytes are particularly abundant in neurodegenerative disorders. As the identification of astrocyte phenotypes progress, their molecular and cellular effects are characterized in a growing array of neuropathologies. 

/pdf/roles-of-neuropathology-associated-reactive-astrocytes-a-26rnccpu.pdf

Roles of neuropathology-associated reactive astrocytes: a systematic review

Stroke remains a major cause of long-term disability and mortality worldwide. The immune system plays an important role in determining the condition of the brain following stroke. As the resident innate immune cells of the central nervous system, microglia are the primary responders in a defense network covering the entire brain parenchyma, and exert various functions depending on dynamic communications with neurons, astrocytes, and other neighboring cells under both physiological or pathological conditions. Microglia activation and polarization is crucial for brain damage and repair following ischemic stroke, and is considered a double-edged sword for neurological recovery. Microglia can exist in pro-inflammatory states and promote secondary brain damage, but they can also secrete anti-inflammatory cytokines and neurotrophic factors and facilitate recovery following stroke. In this review, we focus on the role and mechanisms of microglia-mediated neuroinflammation and neuroplasticity after ischemia and relevant potential microglia-based interventions for stroke therapy.

/pdf/microglia-mediated-neuroinflammation-and-neuroplasticity-28oe3yu6.pdf

Microglia-mediated neuroinflammation and neuroplasticity after stroke

Substance P (SP), an 11-amino-acid neuropeptide, has long been considered an effector of pain. However, accumulating studies have proposed a paradoxical role of SP in anti-nociception. Here, we review studies of SP-mediated nociception and anti-nociception in terms of peptide features, SP-modulated ion channels, and differential effector systems underlying neurokinin 1 receptors (NK1Rs) in differential cell types to elucidate the effect of SP and further our understanding of SP in anti-nociception. Most importantly, understanding the anti-nociceptive SP-NK1R pathway would provide new insights for analgesic drug development.

Ion Channels Involved in Substance P-Mediated Nociception and Antinociception

Human bone marrow-derived mesenchymal stem cells play a role as a vascular pericyte in the reconstruction of human BBB on the angiogenesis microfluidic chip.

Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11b−GFAP+ astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7+ M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation.

Astrocytes Stimulate Microglial Proliferation and M2 Polarization In Vitro through Crosstalk between Astrocytes and Microglia.

Objective The aim of this study was to evaluate the angiogenicity of a combination of BM-EPCs and BM-MSCs in vitro in the presence of SP and its working mechanism. Methods BM-MSCs and BM-EPCs were cocultured with or without SP. ELISA and RT-PCR were performed to detect angiogenic factors such as VEGF and PDGF-BB. N-cadherin was detected by Western blot analysis. The tubular network-forming ability was evaluated by a Matrigel tube-forming assay. Results BM-EPCs coculture with BM-MSCs strongly stimulated the recruitment of BM-MSCs onto the BM-EPC-generated endothelial tubular network. Upon SP treatment, endothelial branching point, tubule length, and tubular recruitment of BM-MSCs were further increased and stabilized. The coculture of BM-EPCs and BM-MSCs synergistically stimulated expression of VEGF, VEGF receptor, N-cadherin, and PDGF-BB, all of which were further enhanced by SP treatment. Blockade of PDGF-BB by its functional blocking antibodies markedly reduced the BM-MSC incorporation into the endothelial tubules. SP-pretreated BM-MSCs were preferentially incorporated into the preformed BM-EPC tubular network. Conclusions BM-EPCs along with SP promote the pericyte-like coverage of BM-MSCs on endothelial tubules possibly through the induction of PDGF-BB.

Endothelial precursor cells stimulate pericyte-like coverage of bone marrow-derived mesenchymal stem cells through platelet-derived growth factor-BB induction, which is enhanced by substance P.

This study aimed to investigate the analgesic effect of substance P (SP) in an animal model of neuropathic pain. An experimental model of neuropathic pain, the chronic constriction injury (CCI) model, was established using ICR mice. An intravenous (i.v.) injection of SP (1 nmole/kg) was administered to the mice to examine the analgesic effects of systemic SP on neuropathic pain. Behavioral testing and immunostaining was performed following treatment of the CCI model with SP. SP attenuated mechanical allodynia in a time-dependent manner, beginning at 1 h following administration, peaking at 1 day post-injection, and decaying by 3 days post-injection. The second injection of SP also increased the threshold of mechanical allodynia, with the effects peaking on day 1 and decaying by day 3. A reduction in phospho-ERK and glial fibrillary acidic protein (GFAP) accompanied the attenuation of mechanical allodynia. We have shown for the first time that i.v. administration of substance P attenuated mechanical allodynia in the maintenance phase of neuropathic pain using von Frey's test, and simultaneously reduced levels of phospho-ERK and GFAP, which are representative biochemical markers of neuropathic pain. Importantly, glial cells in the dorsal horn of the spinal cord (L4- L5) of SP-treated CCI mice, expressed the anti-inflammatory cytokine, IL-10, which was not seen in vehicle saline-treated mice. Thus, i.v. administration of substance P may be beneficial for improving the treatment of patients with neuropathic pain, since it decreases the activity of nociceptive factors and increases the expression of anti-nociceptive factors.

/pdf/intravenous-administration-of-substance-p-attenuates-10al0sn6qj.pdf

Intravenous Administration of Substance P Attenuates Mechanical Allodynia Following Nerve Injury by Regulating Neuropathic Pain-Related Factors.

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Astrocytes Stimulate Microglial Proliferation and M2 Polarization In Vitro through Crosstalk between Astrocytes and Microglia.

Human bone marrow-derived mesenchymal stem cells play a role as a vascular pericyte in the reconstruction of human BBB on the angiogenesis microfluidic chip.

Endothelial precursor cells stimulate pericyte-like coverage of bone marrow-derived mesenchymal stem cells through platelet-derived growth factor-BB induction, which is enhanced by substance P.

Intravenous Administration of Substance P Attenuates Mechanical Allodynia Following Nerve Injury by Regulating Neuropathic Pain-Related Factors.