Brain-derived neurotrophic factor (BDNF), a cognate ligand for the tyrosine kinase receptor B (TrkB) receptor, mediates neuronal survival, differentiation, synaptic plasticity, and neurogenesis. However, BDNF has a poor pharmacokinetic profile that limits its therapeutic potential. Here we report the identification of 7,8-dihydroxyflavone as a bioactive high-affinity TrkB agonist that provokes receptor dimerization and autophosphorylation and activation of downstream signaling. 7,8-Dihydroxyflavone protected wild-type, but not TrkB-deficient, neurons from apoptosis. Administration of 7,8-dihydroxyflavone to mice activated TrkB in the brain, inhibited kainic acid-induced toxicity, decreased infarct volumes in stroke in a TrkB-dependent manner, and was neuroprotective in an animal model of Parkinson disease. Thus, 7,8-dihydroxyflavone imitates BDNF and acts as a robust TrkB agonist, providing a powerful therapeutic tool for the treatment of various neurological diseases.
Brain-derived neurotrophic factor (BDNF) is a cognate ligand for the TrkB receptor. BDNF and serotonin often function in a cooperative manner to regulate neuronal plasticity, neurogenesis, and neuronal survival. Here we show that NAS (N-acetylserotonin) swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. NAS, a precursor of melatonin, is acetylated from serotonin by AANAT (arylalkylamine Nacetyltransferase). NAS rapidly activates TrkB, but not TrkA or TrkC, in a neurotrophin-and MT3 receptor-independent manner. Administration of NAS activates TrkB in BDNF knockout mice. Furthermore, NAS, but not melatonin, displays a robust antidepressant-like behavioral effect in a TrkB-dependent way. Endogenous TrkB is activated in wild-type C3H/f +/+ mice but not in AANAT-mutated C57BL/ 6J mice, in a circadian rhythm; TrkB activation is high at night in the dark and low during the day. Hence, our findings support that NAS is more than a melatonin precursor, and that it can potently activate TrkB receptor.B rain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which includes nerve growth factor, NT-3, NT-4, and NT-5 (1). BDNF binding to TrkB triggers its dimerization through conformational changes and autophosphorylation of tyrosine residues in its intracellular domain, leading to activation of the three major downstream signaling cascades including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, and phospholipase C-γ1 (2, 3). Through these pathways, BDNF mediates a variety of neuronal activities involved in neuronal survival, neurogenesis, synaptic plasticity, and so forth, and is implicated in numerous neurological diseases. For instance, loss of BDNF plays a major role in the pathophysiology of depression, and its restoration that induces neuroplastic changes may underlie the action of antidepressant efficacy (4-7).Daily rhythms in indole metabolism are a unique characteristic of the pineal gland. Pineal serotonin (5-HT) levels are higher during the day than at night. Conversely, pineal N-acetylserotonin (NAS) and melatonin levels are low during the day and high at night (8). The switch between day and night profiles of pineal indoles is predominantly regulated by the activity of arylalkylamine N-acetyltransferase (AANAT), which escalates at night 10-to 100-fold (9). AANAT metabolizes serotonin into NAS. AANAT mRNA is prominently expressed in the pineal gland and retina, and weakly in other regions of brain (10-12). NAS is mainly synthesized in the pineal gland, and is subsequently methylated by hydroxyindole-O-methyltransferase to synthesize melatonin. Until recently, NAS was considered only as the precursor of melatonin in the process of melatonin biosynthesis from serotonin. Melatonin is highly lipophilic and is not stored at significant levels. Accordingly, it is released into the blood immediately upon synthesis. Melatonin's role in the regulation of circadian rhythms and other functions is mediated primarily by me...
7,8-Dihydroxyflavone is a recently identified small molecular tropomyosin-receptor-kinase B (TrkB) agonist. Our preliminary structural activity relationship (SAR) study showed that the 7,8-dihydroxy groups are essential for the agonistic effect. To improve the lead compound's agonistic activity, we have conducted an extensive SAR study and synthesized numerous derivatives. We have successfully identified 4'-dimethylamino-7,8-dihydroxyflavone that displays higher TrkB agonistic activity than the lead. This novel compound also exhibits a more robust and longer TrkB activation effect in animals. Consequently, this new compound reveals more potent anti-apoptotic activity. Interestingly, chronic oral administration of 4'-dimethylamino-7,8-dihydroxyflavone and its lead strongly promotes neurogenesis in dentate gyrus and demonstrates marked antidepressant effects. Hence, our data support that the synthetic 4'-dimethylamino-7,8-dihydroxyflavone and its lead both are orally bioavailable TrkB agonists and possess potent antidepressant effects.
In the medial prefrontal cortex, the prelimbic area is emerging as a major modulator of fear behavior, but the mechanisms remain unclear. Using a selective neocortical knockout mouse, virally mediated prelimbic cortical-specific gene deletion, and pharmacological rescue with a TrkB agonist, we examined the role of a primary candidate mechanism, BDNF, in conditioned fear. We found consistently robust deficits in consolidation of cued fear but no effects on acquisition, expression of unlearned fear, sensorimotor function, and spatial learning. This deficit in learned fear in the BDNF knockout mice was rescued with systemic administration of a TrkB receptor agonist, 7,8-dihydroxyflavone. These data indicate that prelimbic BDNF is critical for consolidation of learned fear memories, but it is not required for innate fear or extinction of fear. Moreover, use of site-specific, inducible BDNF deletions shows a powerful mechanism that may further our understanding of the pathophysiology of fear-related disorders.learning | plasticity | prefrontal cortex | Cre/LoxP | inducible knockout I n healthy individuals, the prefrontal cortex and amygdala are critical for processing fearful and other emotional stimuli and for learning to extinguish fears in situations that are no longer threatening (1, 2). In contrast, patients suffering from posttraumatic stress disorder (PTSD) or anxiety disorders describe persistent anxiety-provoking memories that are severely debilitating and cannot be extinguished (3-6). Therefore, the experimental analysis of fear modulation and extinction is critical for an understanding of the neurobiology of fear inhibition. The medial prefrontal cortex (mPFC) is suggested to be an important region for the regulation of fear (7-13). Although it is established that the infralimbic cortex (IL) region of the mPFC is required for fear extinction (9,11,14), the role of the prelimbic cortex (PL) in the regulation of fear learning and extinction are yet to be fully understood. Although previous studies have shown that lesions of the PL do not affect acquisition or expression of fear (7, 9, 15), inactivation reduces freezing behavior in previously fear-conditioned rats (16). Additionally, activation of PL neurons are required for the expression of previously learned fears (17, 18), and microstimulation of the PL potentiates expression of conditioned fear (19). Moreover, these neurons have also shown plasticity after fear conditioning (18,20,21) and have sustained activity to conditioned tones (22). Overall, these data suggest that the PL is necessary for the expression of previously learned fear, but the mechanisms remain unclear.One potential candidate may be BDNF and its receptor tyrosine kinase receptor B (TrkB); they are known to regulate neuronal structure and function and are important for synaptic plasticity (23-26). Additionally, in vivo studies have shown a role for BDNF in learning and memory, including fear conditioning (27-31). More specifically, we have previously shown that disruption of TrkB activat...
Terminally differentiated neurons are unable to reenter the cell cycle. Aberrant cell cycle activation provokes neuronal cell death, whereas cell cycle inhibition elevates neuronal survival. However, the molecular mechanism regulating the cell cycle and cell death in mature neurons remains elusive. Here we show that SRPK2, a protein kinase specific for the serine/arginine (SR) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin D1. Akt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events. We find that SRPK2 is phosphorylated in ischemia-attacked brain, correlating with the observed increase in cyclin D1 levels. Hence, phosphatidylinositol 3-kinase/Akt mediates the cell cycle and cell death machinery in the nervous system through phosphorylation of SRPK2.In the central nervous system the nascent neuroblasts leave ventricular zone or subventricular zone and migrate to the destination where they differentiate and become permanently post-mitotic cells (1). It is well established that terminally differentiated neurons are unable to reenter the cell cycle, but accumulating evidence has demonstrated the up-regulation of cell cycle regulatory proteins in degenerating neurons of Alzheimer disease (AD) 2 brain (2). Elevated levels of Cdc2, Cdk4, p16, Ki-67, cyclin B1, and cyclin D have been found in pathologically affected or vulnerable neurons in AD (3-7). Moreover, several of these regulators have been observed in vulnerable neurons before lesion formation (8). Together these findings suggest that the activity of certain cell cycle regulators plays a critical upstream role in the AD neurodegenerative process. Greene and co-workers (9 -12) have shown that drugs that block cell cycle advances are efficient in preventing the death of PC12 cells as well as sympathetic neurons. Dominant negative forms of the Cdk4 and Cdk6 preventing the cell death induced by camptothecin (a topoisomerase inhibitor) are effectively blocked by the G 1 /S blockers, such as deferoxamine and mimosine, as well as by the cyclin-dependent kinases (Cdk) inhibitors flavopiridol and olomoucine. In addition, they show that neurons treated with DNA-damaging agents such as UV irradiation or camptothecin also require cyclin D and Cdk4/6 activity to induce neuronal death (13). Thus, this evidence supports that mature neurons might retain certain elements of the cell cycle and have the capability of reactivating additional aspects of the replication mechanism when under stresses. Any events that force a mature neuron back into the cell cycle are lethal rather than mitogenic for the neuron.SRPK, a family of cell cycle-regulated protein kinases, phosphorylate serine/arginine (SR) domain-containing protein...
Ischemia and seizure cause excessive neuronal excitation that is associated with brain acidosis and neuronal cell death. However, the molecular mechanism of acidification-triggered neuronal injury is incompletely understood. Here, we show that asparagine endopeptidase (AEP) is activated under acidic condition, cuts SET, an inhibitor of DNase, and triggers DNA damage in brain, which is inhibited by PIKE-L. SET, a substrate of caspases, was cleaved by acidic cytosolic extract independent of caspase activation. Fractionation of the acidic cellular extract yielded AEP that is required for SET cleavage. We found that kainate provoked AEP activation and SET cleavage at N175, triggering DNA nicking in wild-type, but not AEP null, mice. PIKE-L strongly bound SET and prevented its degradation by AEP, leading to resistance of neuronal cell death. Moreover, AEP also mediated stroke-provoked SET cleavage and cell death in brain. Thus, AEP might be one of the proteinases activated by acidosis triggering neuronal injury during neuroexcitotoxicity or ischemia.
Oxidative stress can induce apoptosis through activation of MstI, subsequent phosphorylation of FOXO and nuclear translocation. MstI is a common component of apoptosis initiated by various stresses. MstI kinase activation requires autophosphorylation and proteolytic degradation by caspases. FOXO2 (forkhead box O; forkhead members of the O class) are transcription factors. FOXO factors mediate cell death by regulating numerous apoptotic genes transcription (1-3). FOXO factors are insulin-sensitive transcription factors with a variety of downstream targets and interacting partners. Insulinmediated inhibition of FOXO factors is predominantly regulated through a shuttling mechanism that distributes FOXO localization to the cytoplasm, thereby terminating its transcriptional function (4). FOXO factors contain three highly conserved putative Akt recognition motifs (RXRXX(S/T), where X denotes any residue), two at the N and C termini, respectively, and one located in the forkhead domain. All FOXO proteins require Akt phosphorylation in the N terminus and in the forkhead domain to translocate from the nucleus to the cytoplasm (5). The two phosphorylated residues are essential components for translocation, as they influence the NLS (nuclear localization sequence) function and the association with 14-3-3 proteins (2). Recently, Bonni and co-workers demonstrated that MstI mediates oxidative stress-induced neuronal apoptosis through FOXO factors by phosphorylating FOXO3 on Ser 207 . This phosphorylation triggers its nuclear translocation and disrupting the association between 14-3-3 and FOXO in the cytoplasm (6).MstI belongs to class II GC (protein Ser/Thr) kinase (7), which contains 487 residues and predominantly resides in the cytoplasm. MstI consists of an N-terminal catalytic domain in the Ste20 class, followed by a non-catalytic tail comprising of an autoinhibitory domain and a coiled-coil domain that mediates dimerization (8). It has been suggested that, physiologically, MstI exists as an autoinhibitory homodimer that is activated after post-translational modification such as phosphorylation and/or cleavage. Although caspase-mediated cleavage removes the C-terminal regulatory domain, which is associated with an increase in MstI activity, there is evidence that caspase-mediated cleavage alone cannot activate MstI and both phosphorylation and proteolysis are necessary to activate fully this enzyme (9 -11). Indeed, Lee et al. (12) (9,11). Of these, Thr 183 and Thr 187 appear to be essential for kinase activity (11). It has been proposed before that phosphorylation of MstI on Thr 183 and possibly Thr 187 is induced by an existing active MstI (11). Overexpression of MstI alone is sufficient to initiate apoptosis in various cells, which involves activation of SAPK (stress-activated protein kinase)/JNK (13), p53 (14), FOXO (6). MstI cycles rapidly and continuously through the nucleus (6, 15), and associates with DAP-4 (death-associated protein-4) in the nucleus (14), where the catalytic fragment generated during apoptosi...
Nerve growth factor (NGF) binds to TrkA receptor and triggers activation of numerous signaling cascades, which play critical roles in neuronal plasticity, survival, and neurite outgrowth. To mimic NGF functions pharmacologically, we developed a high-throughput screening assay to identify small-molecule agonists for TrkA receptor. The most potent compound, gambogic amide, selectively binds to TrkA, but not TrkB or TrkC, and robustly induces its tyrosine phosphorylation and downstream signaling activation, including Akt and MAPKs. Further, it strongly prevents glutamate-induced neuronal cell death and provokes prominent neurite outgrowth in PC12 cells. Gambogic amide specifically interacts with the cytoplasmic juxtamembrane domain of TrkA receptor and triggers its dimerization. Administration of this molecule in mice substantially diminishes kainic acid-triggered neuronal cell death and decreases infarct volume in the transient middle cerebral artery occlusion model of stroke. Thus, gambogic amide might not only establish a powerful platform for dissection of the physiological roles of NGF and TrkA receptor but also provide effective treatments for neurodegenerative diseases and stroke.neurotrophic effect ͉ nerve growth factor ͉ ligand ͉ receptor dimerization
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