MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia

Infantino, Rosmara; Schiano, Concetta; Luongo, Livio; Paino, Salvatore; Mansueto, Gelsomina; Boccella, Serena; Guida, Francesca; Ricciardi, Flavia; Iannotta, Monica; Belardo, Carmela; Marabese, Ida; Pieretti, Gorizio; Serra, Nicola; Napoli, Claudio; Maione, Sabatino

doi:10.1016/j.nbd.2022.105611

Cited by 32 publications

(21 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Its functions include nourishing damaged neurons, regulating neural plasticity, depicting a vital role in the survival, differentiation, growth, and postinjury repair of neurons, and participating in the initiation and development of depression, regarded as a landmark indicator for the diagnosis of depression [ 62 , 63 ]. Many studies have revealed that the expression of BDNF and its high-affinity receptor TrkB protein in the thalamus decrease after PSD, indicating PSD occurrence is tightly associated with BDNF level, and the lesser the production of BDNF, the more likely PSD will occur [ 64 , 65 ]. Infantino et al found that the MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating the activation of microglia [ 66 ].…”

Section: Ischemic Stroke and Depressionmentioning

confidence: 99%

Microglia Involves in the Immune Inflammatory Response of Poststroke Depression: A Review of Evidence

Xia

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Poststroke depression (PSD) does not exist before and occurs after the stroke. PSD can appear shortly after the onset of stroke or be observed in the weeks and months after the acute or subacute phase of stroke. The pathogenesis of PSD is unclear, resulting in poor treatment effects. With research advancement, immunoactive cells in the central nervous system, particularly microglia, play a role in the occurrence and development of PSD. Microglia affects the homeostasis of the central nervous system through various factors, leading to the occurrence of depression. The research progress of microglia in PSD has been summarized to review the evidence regarding the pathogenesis and treatment target of PSD in the future.

show abstract

Section: Ischemic Stroke and Depressionmentioning

confidence: 99%

Microglia Involves in the Immune Inflammatory Response of Poststroke Depression: A Review of Evidence

Xia

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…Over the past decades, the decline in stroke mortality has been accompanied by a rise in stroke incidence at younger ages, leading to an increased survival among stroke patients [36]. These survivors suffer from many complications, with an estimated incidence ranging between 24.2-95% [36], such as movement, perceptual, emotional and cognitive impairments, which place an enormous burden on society and families [5,37,38].…”

Section: Discussionmentioning

confidence: 99%

“…Reperfusion or reconstruction of blood ow in the ischemic region is the key treatment strategy for strokeassociated ischemic brain injury [3]. But over half of stroke survivors require rehabilitation for residual neurological de cits, perceptual and emotional disorders [2,4,5]. The damage caused by cerebral ischemia consists of different pathological mechanisms in which excitotoxicity, a disturbed homeostasis of excitatory amino acids leading to stroke progression, plays a vital role [6,7].…”

Section: Introductionmentioning

confidence: 99%

Activation of CREB-BDNF Pathway in Pyramidal Neurons in the Hippocampus Improves the Neurological Outcome of Mice with Ischemic Stroke

et al. 2022

View full text Add to dashboard Cite

Cerebral ischemia is characterized by several pathological reaction evolving over time. Hyperactivation of glutamatergic neurons is the main factor leading to excitotoxicity which potentiates oxidative stress and triggers the mechanisms of neural apoptosis after cerebral ischemia. However, it is unclear whether glutamate in the ventral hippocampal Cornus Ammonis 1 (vCA1) acts a part in neurological de cits, pain perception, anxiety and depression induced by ischemic-stroke. We investigated the effects of chemogenetic inhibition or activation of vCA1 pyramidal neurons which are mainly glutamatergic neurons on sequelae induced by cerebral ischemia. Our results revealed that inhibition of vCA1 pyramidal neurons by chemogenetics alleviated neurological de cits, pain perception, anxiety and depression caused by cerebral ischemia in mice, but activation of vCA1 pyramidal neurons had limited effects. Moreover, we found that stroke was accompanied by decreased levels of cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in vCA1, which are modulated by glutamate.In this study, overexpression of CREB protein in pyramidal neurons in vCA1 by AAV virus signi cantly upregulated the content of BDNF and ameliorated the dysfunction induced by ischemic-stroke. Our results demonstrated activation of CREB-BDNF pathway in vCA1 pyramidal neurons signi cantly improved neurological de cits, pain perception, anxiety and depression induced by ischemic-stroke.

show abstract

“…Inhibition of local inflammatory cytokines (IL-1β, TNF-α) and chemokines (CXCL12/CXCR4) signaling as well as glial cell activation in the damaged thalamus also markedly ameliorated CPSP symptoms transiently [ 10 – 14 ]. Notably, microglia activation has also been implicated in thalamic hemorrhage-induced depression [ 15 ], suggesting that targeting microglia-mediated inflammatory cascades may be rational for treating CPSP and emotional comorbidity. Our previous study revealed that hypoxia-inducible factor-1 alpha (HIF-1α), an oxygen-dependent transcriptional activator, was the initiator of neuroinflammation following thalamic hemorrhagic stroke and was involved in the genesis of CPSP by boosting glial cell activation and driving the expression of pro-inflammatory cytokines [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Stellate ganglion block ameliorated central post-stroke pain with comorbid anxiety and depression through inhibiting HIF-1α/NLRP3 signaling following thalamic hemorrhagic stroke

Shi

Jing

Xue

et al. 2023

J Neuroinflammation

View full text Add to dashboard Cite

Background Central post-stroke pain (CPSP) is an intractable and disabling central neuropathic pain that severely affects patients’ lives, well-being, and socialization abilities. However, CPSP has been poorly studied mechanistically and its treatment remains challenging. Here, we used a rat model of CPSP induced by thalamic hemorrhage to investigate its underlying mechanisms and the effect of stellate ganglion block (SGB) on CPSP and emotional comorbidities. Methods Thalamic hemorrhage was produced by injecting collagenase IV into the ventral-posterolateral nucleus (VPL) of the right thalamus. The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Behavioral tests were carried out to examine depressive and anxiety-like behaviors including the open field test (OFT), elevated plus maze test (EPMT), novelty-suppressed feeding test (NSFT), and forced swim test (FST). The peri-thalamic lesion tissues were collected for immunofluorescence, western blotting, and enzyme-linked immunosorbent assay (ELISA). Genetic knockdown of thalamic hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) with microinjection of HIF-1α siRNA and NLRP3 siRNA into the VPL of thalamus were performed 3 days before collagenase injection into the same regions. Microinjection of lificiguat (YC-1) and MCC950 into the VPL of thalamus were administrated 30 min before the collagenase injection in order to inhibited HIF-1α and NLRP3 pharmacologically. Repetitive right SGB was performed daily for 5 days and laser speckle contrast imaging (LSCI) was conducted to examine cerebral blood flow. Results Thalamic hemorrhage caused persistent mechanical allodynia and anxiety- and depression-like behaviors. Accompanying the persistent mechanical allodynia, the expression of HIF-1α and NLRP3, as well as the activities of microglia and astrocytes in the peri-thalamic lesion sites, were significantly increased. Genetic knockdown of thalamic HIF-1α and NLRP3 significantly attenuated mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. Further studies revealed that intra-thalamic injection of YC-1, or MCC950 significantly suppressed the activation of microglia and astrocytes, the release of pro-inflammatory cytokines, the upregulation of malondialdehyde (MDA), and the downregulation of superoxide dismutase (SOD), as well as mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. In addition, repetitive ipsilateral SGB significantly restored the upregulated HIF-1α/NLRP3 signaling and the hyperactivated microglia and astrocytes following thalamic hemorrhage. The enhanced expression of pro-inflammatory cytokines and the oxidative stress in the peri-thalamic lesion sites were also reversed by SGB. Moreover, LSCI showed that repetitive SGB significantly increased cerebral blood flow following thalamic hemorrhage. Most strikingly, SGB not only prevented, but also reversed the development of mechanical allodynia and anxiety- and depression-like behaviors induced by thalamic hemorrhage. However, pharmacological activation of thalamic HIF-1α and NLRP3 with specific agonists significantly eliminated the therapeutic effects of SGB on mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. Conclusion This study demonstrated for the first time that SGB could improve CPSP with comorbid anxiety and depression by increasing cerebral blood flow and inhibiting HIF-1α/NLRP3 inflammatory signaling.

show abstract

MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia

Cited by 32 publications

References 73 publications

Microglia Involves in the Immune Inflammatory Response of Poststroke Depression: A Review of Evidence

Microglia Involves in the Immune Inflammatory Response of Poststroke Depression: A Review of Evidence

Activation of CREB-BDNF Pathway in Pyramidal Neurons in the Hippocampus Improves the Neurological Outcome of Mice with Ischemic Stroke

Stellate ganglion block ameliorated central post-stroke pain with comorbid anxiety and depression through inhibiting HIF-1α/NLRP3 signaling following thalamic hemorrhagic stroke

Contact Info

Product

Resources

About