TRPC channels: Structure, function, regulation and recent advances in small molecular probes.

Traumatic brain injury (TBI) is a leading major cause of morbidity and mortality in youth and individuals under 45 year age. A wide variety of cellular and molecular mechanisms have been identified contributing to the pathogenesis of TBI. A better understanding of the pathophysiology behind TBI is essential for providing more effective treatment. Excitotoxicity as one of the secondary molecular events is a major contributing factor in apoptosis and neuronal death following the initial injury in TBI. Excitotoxicity is the rapid overload and influx of calcium into the cell cytoplasm, activating a series of deleterious signaling cascades causing the cell to undergo apoptosis. Conventional understanding is that the rapid influx of calcium is initiated through glutamate release. However, there are overlooked glutamate-independent mechanisms that cause the rapid calcium influx into the neuronal cytoplasm, evoking or contributing to excitotoxicity. Therefore, the focus of this review will be on the role of the glutamate-independent excitotoxic mechanisms of the mechanosensitive response of NMDA receptors, mechanoporation of the cell membrane, ischemia, and the release of calcium from intracellular stores. In conclusion, the shear and stretch forces during a TBI event may result in the mechanosensitive activation of NMDA receptors which contribute to glutamate-independent excitotoxicity.

The overlooked aspect of excitotoxicity: Glutamate‐independent excitotoxicity in traumatic brain injuries

The nonselective monovalent cation channel transient receptor potential melastatin 4 (Trpm4) is transcriptionally upregulated in neural and vascular cells in animal models of brain infarction. It associates with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which have critical roles in cytotoxic edema, cell death, blood-brain barrier breakdown, and vasogenic edema. We examined Trpm4 expression in postmortem brain specimens from 15 patients who died within the first 31 days of the onset of focal cerebral ischemia. We found increased Trpm4 protein expression in all cases using immunohistochemistry; transcriptional upregulation was confirmed using in situ hybridization of Trpm4 messenger RNA. Transient receptor potential melastatin 4 colocalized and coassociated with Sur1 within ischemic endothelial cells and neurons. Coexpression of Sur1 and Trpm4 in necrotic endothelial cells was also associated with vasogenic edema indicated by upregulated perivascular tumor necrosis factor, extravasation of serum immunoglobulin G, and associated inflammation. Upregulated Trpm4 protein was present up to 1 month after the onset of cerebral ischemia. In a rat model of middle cerebral artery occlusion stroke, pharmacologic channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, mitigated perivascular tumor necrosis factor labeling. Thus, upregulated Sur1-Trpm4 channels and associated blood-brain barrier disruption and cerebral edema suggest that pharmacologic targeting of this channel may represent a promising therapeutic strategy for the clinical management of patients with cerebral ischemia.

Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts.

Traumatic brain injury (TBI) represents an important problem of global health. The damage related to TBI is first due to the direct injury and then to a secondary phase in which neuroinflammation plays a key role. NLRP3 inflammasome is a component of the innate immune response and different diseases, such as neurodegenerative diseases, are characterized by NLRP3 activation. This review aims to describe NLRP3 inflammasome and the consequences related to its activation following TBI. NLRP3, caspase-1, IL-1β, and IL-18 are significantly upregulated after TBI, therefore, the use of nonspecific, but mostly specific NLRP3 inhibitors is useful to ameliorate the damage post-TBI characterized by neuroinflammation. Moreover, NLRP3 and the molecules associated with its activation may be considered as biomarkers and predictive factors for other neurodegenerative diseases consequent to TBI. Complications such as continuous stimuli or viral infections, such as the SARS-CoV-2 infection, may worsen the prognosis of TBI, altering the immune response and increasing the neuroinflammatory processes related to NLRP3, whose activation occurs both in TBI and in SARS-CoV-2 infection. This review points out the role of NLRP3 in TBI and highlights the hypothesis that NLRP3 may be considered as a potential therapeutic target for the management of neuroinflammation in TBI.

https://www.mdpi.com/1422-0067/21/17/6204/pdf

The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury.

Hypoxic-ischemic encephalopathy (HIE) is a serious birth complication with high incidence in both advanced and developing countries. Children surviving from HIE often have severe long-term sequela including cerebral palsy, epilepsy, and cognitive disabilities. The severity of HIE in infants is tightly associated with increased IL-1β expression and astrocyte activation which was regulated by transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel in the TRP family. Neonatal hypoxic ischemia (HI) and oxygen-glucose deprivation (OGD) were used to simulate HIE in vivo and in vitro. Primarily cultured astrocytes were used for investigating the expression of glial fibrillary acidic protein (GFAP), IL-1β, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and activation of the nucleotide-binding, oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome by using Western blot, q-PCR, and immunofluorescence. Brain atrophy, infarct size, and neurobehavioral disorders were evaluated by Nissl staining, 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and neurobehavioral tests (geotaxis reflex, cliff aversion reaction, and grip test) individually. Astrocytes were overactivated after neonatal HI and OGD challenge. The number of activated astrocytes, the expression level of IL-1β, brain atrophy, and shrinking infarct size were all downregulated in TRPV1 KO mice. TRPV1 deficiency in astrocytes attenuated the expression of GFAP and IL-1β by reducing phosphorylation of JAK2 and STAT3. Meanwhile, IL-1β release was significantly reduced in TRPV1 deficiency astrocytes by inhibiting activation of NLRP3 inflammasome. Additionally, neonatal HI-induced neurobehavioral disorders were significantly improved in the TRPV1 KO mice. TRPV1 promotes activation of astrocytes and release of astrocyte-derived IL-1β mainly via JAK2-STAT3 signaling and activation of the NLRP3 inflammasome. Our findings provide mechanistic insights into TRPV1-mediated brain damage and neurobehavioral disorders caused by neonatal HI and potentially identify astrocytic TRPV1 as a novel therapeutic target for treating HIE in the subacute stages (24 h).

/pdf/trpv1-mediates-astrocyte-activation-and-interleukin-1b-2gwh3um0nj.pdf

TRPV1 mediates astrocyte activation and interleukin-1β release induced by hypoxic ischemia (HI).

Brain-derived neurotrophic factor (BDNF) is well known to play a critical role in cognition. Its role in mood disorders, including post stroke depression (PSD), is also recognized with more evidence surfacing. In patients with PSD, their serum BNDF level is lower than in those without depression. Furthermore, antidepressants could enhance BDNF expression in the brain, resulting in an alleviation of depression symptoms. Such therapeutic effect can be abolished in animals with the BDNF gene deleted. In PSD patients, the presence of stroke may contribute to the development of depression, including affecting the expression of BDNF. However, the mechanisms of BDNF in the development of PSD remain largely unknown. Lower BDNF levels may have existed in some patients before stroke onset, making them vulnerable to develop depressive symptoms. Meanwhile, the hypoxic environment induced by stroke could possibly downregulate BDNF expression in the brain. Current antidepressant treatments are not specific for PSD and there is a lack of treatments to address the linkage between stroke and PSD. This review summarizes the current knowledge of BDNF in PSD. By regulating BDNF expression, a synergistic effect may be achieved when such treatments are applied together with existing antidepressants.

Brain-derived neurotrophic factor and post-stroke depression.

Transient receptor potential (TRP) channels have been increasingly implicated in the pathological mechanisms of CNS disorders TRP expression has been detected in neurons, astrocytes, oligodendrocytes, microglia, and ependymal cells as well as in the cerebral vascular endothelium and smooth muscle In stroke, TRPC3/4/6, TRPM2/4/7, and TRPV1/3/4 channels have been found to participate in ischemia-induced cell death, whereas other TRP channels, in particular those expressed in nonneuronal cells, have been less well studied This review summarizes the current knowledge on the expression and functions of the TRP channels in various cell types in the brain and our current understanding of TRP channels in stroke pathophysiology In an aging society, the occurrence of stroke is expected to increase steadily, and there is an urgent requirement to improve the current stroke management strategy Therefore, elucidating the roles of TRP channels in stroke could shed light on the development of novel therapeutic strategies and ultimately improve stroke outcome © 2014 Wiley Periodicals, Inc

Brain transient receptor potential channels and stroke

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Brain-derived neurotrophic factor and post-stroke depression.

Brain transient receptor potential channels and stroke