Activation of TrkB/Akt signaling by a TrkB receptor agonist improves long-term histological and functional outcomes in experimental intracerebral hemorrhage

Abstract

Background Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades that contribute to secondary neuronal damage. Tropomyosin-related kinase receptor B (TrkB) signaling plays a crucial role in promoting neuronal survival following brain damage. Methods The present study investigated the protective effects and underlying mechanisms of TrkB activation by the specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), in a model of collagenase-induced ICH and in neuronal cultures. Mice subjected to collagenase-induced ICH were intraperitoneally injected with either 7,8-DHF or vehicle 10 min after ICH and, subsequently, daily for 3 days. Behavioral studies, brain edema measurement, and histological analysis were conducted. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed by western blots. Results Treatment with 20 mg/kg 7,8-DHF significantly improved functional recovery and reduced brain damage up to 28 days post-ICH. Reduction in neuronal death, apoptosis, and brain edema were also observed in response to 7,8-DHF treatment at 3 days post-ICH. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt (Ser473/Thr308) at 1 and 3 days, but had no effect on Erk 44/42 phosphorylation. 7,8-DHF also enhanced the phosphorylation of Ask-1 Ser967 and FOXO-1, downstream targets of Akt at 1 and 3 days. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels at 1 day. In primary cultured neurons stimulated with hemin, 7,8-DHF promoted survival and reduced apoptosis. Furthermore, delaying the administration of 7,8-DHF to 3 h post-ICH reduced brain tissue damage and neuronal death. Conclusions Our findings demonstrate that the activation of TrkB signaling by 7,8-DHF protects against ICH via the Akt, but not the Erk, pathway. These data provide new insights into the role of TrkB signaling deficit in the pathophysiology of ICH and highlight TrkB/Akt as possible therapeutic targets in this disease.

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

“…Various forms of cell death have been identified after ICH, including apoptosis, necrosis, and autophagy in humans and experimental animals, and autophagic cell death in animal models [31][32][33]. Although inhibiting apoptosis, necrosis, and autophagy can improve outcomes in animals subjected to experimental ICH, no successful clinical trials using cell-death inhibitor monotherapy have been reported [34][35][36]. These facts suggest that multiple forms of cell death other than those mentioned above may occur after ICH and contribute collectively to neuronal death.…”

7,8-dihydroxyflavone Improves Neuropathological Changes in the Brain of Tg26 Mice, A Model for HIV-associated Neurocognitive Disorder

“…TrkB is a receptor of BDNF that plays a role in stimulating neuronal survival, morphogenesis, and plasticity [44], and DHF upregulates TrkB phosphorylation via the Akt pathway [45]. The PI3K/Akt signaling pathway protects against apoptosis and promotes neuronal survival [45]. DHF activates the TrkB receptor and the PI3K/AKT and MAPK pathway in hippocampal neurons [46].…”

Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System

“…(Sivandzade et al, 2019;Hannan et al, 2020a). Inappropriate levels of antiapoptotic proteins [e.g., Bcl-2 (B-cell lymphoma 2)] and proapoptotic proteins [e.g., Bax (Bcl-2-associated X protein)] contribute to mitochondrial dysfunction and OSinduced apoptosis (Wu et al, 2019). In addition, the reestablishment of blood supply immediately after ischemia exposes brain tissue to excess oxygen, which exacerbates ROS production, which, in turn, induces further OS-associated injury, lipid peroxidation, protein oxidation, and intracellular DNA damage (Kishimoto et al, 2019;Sivandzade et al, 2019).…”

“…BDNF binds TrkB and helps maintain neuronal survival and synaptic plasticity by activating canonical signaling pathways, that is, the PI3K/Akt pathway, the mitogen-activated protein kinase (MAPK) pathway, and the phospholipase C-γ (PLCγ) pathway (Kowiański et al, 2018). The PI3K/Akt signaling pathway is the major TrkB-mediated survival pathway that promotes neuronal survival and protects against apoptosis (Wu et al, 2019). Activated Akt also controls cell survival by maintaining a balance between pro-apoptotic and anti-apoptotic proteins (Sussman, 2009).…”

“…As a consequence, a portion of the brain experiences oxygen and nutrient insufficiencies, which cause depolarization of neuronal membranes and glutamate surge into synapses, resulting in a cascade of events, including calcium overload, dissipation of mitochondrial membrane potentials, OS, and inflammation ( Sivandzade et al, 2019 ; Hannan et al, 2020a ). Inappropriate levels of antiapoptotic proteins [e.g., Bcl-2 (B-cell lymphoma 2)] and proapoptotic proteins [e.g., Bax (Bcl-2-associated X protein)] contribute to mitochondrial dysfunction and OS-induced apoptosis ( Wu et al, 2019 ). In addition, the re-establishment of blood supply immediately after ischemia exposes brain tissue to excess oxygen, which exacerbates ROS production, which, in turn, induces further OS-associated injury, lipid peroxidation, protein oxidation, and intracellular DNA damage ( Kishimoto et al, 2019 ; Sivandzade et al, 2019 ).…”