Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats

Gudasheva, T. A.; Povarnina, P. Yu.; Logvinov, I. O.; Антипова, Т. А.; Середенин, С. Б.

doi:10.2147/dddt.s118768

Cited by 50 publications

(32 citation statements)

References 22 publications

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“…LM binding to TrkB lead to the activation of the TrkB-ERK1/2 pathway, similar to previous reports from in vitro studies that peptide mimetics of either loop I, III, or IV of BDNF can induce AKT and ERK phosphorylation ( 58, 59 ). TrkB activation also phosphorylates residue Y816 on its intracellular domain, which permits recruitment and activation of the PLCγ1 pathway, which activates numerous pathways including the Ca 2+ /calmodulin-dependent kinases ( 60, 61 ).…”

Section: Discussionsupporting

confidence: 90%

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

Kipnis

Sullivan

Carter

et al. 2019

Preprint

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34Refractory neonatal seizures do not respond to first-line anti-seizure medications (ASMs) 35 like phenobarbital (PB), a positive allosteric modulator for GABAA receptors, the most widely 36 used ASM to treat neonatal seizures. GABAA receptor-mediated inhibition is dependent upon 37 neuronal chloride regulation. The electroneutral cation-chloride transporter KCC2 mediates 38 neuronal chloride extrusion; an age-dependent increase of KCC2 expression enables the shift of 39 GABAergic signaling from depolarizing to hyperpolarizing. BDNF-TrkB activation following 40 excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. This 41 study investigated the efficacy of partial and full TrkB agonists; LM22A-4 (LM), HIOC and 42 Deoxygedunin (DG) respectively, on PB-refractory seizures, post-ischemic TrkB-pathway 43 activation, and KCC2 membrane stability in a P7 CD-1 mouse model of refractory neonatal 44 seizures. Anti-seizure efficacy was determined by quantifying seizure burdens with continuous 45 video-EEG. LM rescued PB-refractory seizures in a sexually dimorphic manner. LM anti-seizure 46 efficacy was associated with a significant reduction in the post-ischemic phosphorylation of 47 TrkB at Y816, a site known to mediate post-ischemic KCC2 hypofunction via PLCγ1 activation. 48 LM additionally rescued ischemia-induced pKCC2-S940 dephosphorylation preserving its 49 membrane stability. HIOC and DG, two novel full TrkB agonists, also rescued PB-refractoriness 50 and post-ischemic TrkB-PLCγ1 pathway activation. Additionally, chemogenetic inactivation of 51 TrkB significantly reduced post-ischemic neonatal seizure burdens at P7. Developmental 52 expression profiles of TrkB and KCC2 in naïve pups identified developmental differences that 53 may underlie the sex-dependent variance in anti-seizure efficacy. These results support a novel 54 role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures. 55 56 65 (KCC2) in a mouse model of acute neonatal ischemia associated with phenobarbital (PB)-66 refractory seizures (5). 67The electroneutral cation-chloride transporter KCC2 is the primary neuronal Clextruder 68 and enables hyperpolarizing GABAergic inhibition in the brain. The residue Ser940 (S940) on 69 the C-terminus of KCC2 is associated with its membrane stability and chloride extrusion 70 capacity (6, 7). The developmental switch in GABAergic signaling from depolarizing to 71 hyperpolarizing (8) is enabled by an age-dependent increase of KCC2 expression (9). In the 72 neonatal period, KCC2 expression is low and GABA is depolarizing (8-10). In addition, KCC2 73 is susceptible to degradation following excitotoxic injury (2, 11, 12). In our characterized CD-1 74 mouse model of ischemic neonatal seizures, KCC2 underwent degradation and 75 dephosphorylation of residue S940 (5). This rendered the ASM PB inefficacious (5), as PB is a 76 positive allosteric modulator of GABAA receptors (13). Prevention of BDNF-TrkB mediated 77 KCC2 hypofunction rescued PB-refractori...

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Section: Discussionsupporting

confidence: 90%

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

Kipnis

Sullivan

Carter

et al. 2019

Preprint

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“…Based on the sequence of BDNF loop 4 and loop 1 β-turn, Gudasheva and colleagues have recently created two dimeric dipeptides, which mimic full-length BDNF. They exhibited varied abilities to activate the Akt and ERK pathways and exhibited therapeutic effects in the rat MCAO model [116].…”

Section: Improvement Of Bdnf Delivery and The Development Of New Trkbmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities

et al. 2020

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With the rise in the aging global population, stroke comorbidities have become a serious health threat and a tremendous economic burden on human society. Current therapeutic strategies mainly focus on protecting neurons from cytotoxic damage at the acute phase upon stroke onset, which not only is a difficult way to ameliorate stroke symptoms but also presents a challenge for the patients to receive effective treatment in time. The brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the adult brain, which possesses a remarkable capability to repair brain damage. Recent promising preclinical outcomes have made BDNF a popular late-stage target in the development of novel stroke treatments. In this review, we aim to summarize the latest progress in the understanding of the cellular/molecular mechanisms underlying stroke pathogenesis, current strategies and difficulties in drug development, the mechanism of BDNF action in poststroke neurorehabilitation and neuroplasticity, and recent updates in novel therapeutic methods.

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“…We have developed low-molecular-weight compounds that mimic the beta-turns of some BDNF loops and experimentally proved that they selectively activate post-receptor cascades [12, 13]. In this case, BDNF mimetics selectively activating either PI3K/AKT or MAPK/ERK were found not to exhibit antidepressant activity, which indicates that both post-receptor signaling pathways are essential for this activity.…”

Section: Introductionmentioning

confidence: 99%

“…Western blot analysis revealed that GSB-106 activates BDNF-specific TrkB receptors and their post-receptor signaling pathways MAPK/ERK and PI3K/AKT [12, 16]. GSB-106 exhibited pronounced antidepressant activity in a rodent test battery at a dose of 0.1 to 1.0 mg/kg administered intraperitoneally [15, 17].…”

Section: Introductionmentioning

confidence: 99%

Antidepressant Effect of an Orally Administered Dipeptide Mimetic of the Brain-Derived Neurotrophic Factor

Povarnina¹,

Garibova²,

Gudasheva³

et al. 2018

Acta Naturae

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Involvement of BDNF in the regulation of neuroplasticity and neurogenesis in the hippocampus, impairment of which underlies the pathophysiology of depression, makes this endogenous protein a promising object for the development of new-generation antidepressants with a neurophysiologically based mechanism of action. A low-molecular-weight BDNF mimetic, GSB-106 (a substituted dimeric dipeptide, bis-(N-monosuccinyl- L-seryl-L-lysine) hexamethylenediamide), was designed and synthesized at the Zakusov Institute of Pharmacology. GSB-106 was found to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways MAPK/ERK and PI3K/AKT. GSB-106 exhibited pronounced antidepressant activity in a rodent test battery at a dose of 0.1 to 1.0 mg/kg administered intraperitoneally. Because oral administration is preferable in the treatment of depression, which is associated with a prolonged duration and outpatient character of pharmacotherapy, we examined the antidepressant properties of GSB-106 administered orally as a pharmaceutical substance (PS) and in tablet dosage form (TDF). In the study, we used the Porsolt forced swim test in rats; a conventional antidepressant, Amitriptyline, was used as a reference drug. The antidepressant activity of GSB-106 was found to retain upon oral administration and to manifest at doses of 0.5–5.0 mg/kg for PS and 0.01–5.0 mg/kg for TDF. The effective dose of TDF was 50-fold lower than that of PS, and the efficacy of tableted GSB-106 exceeded that of Amitriptyline, the “gold standard” in antidepression care. Therefore, GSB-106, both as a substance and as a tablet dosage form, exhibits antidepressant activity when administered orally, which makes it a promising antidepressant agent, the first in the class of BDNF mimetics.

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Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats

Cited by 50 publications

References 22 publications

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities

Antidepressant Effect of an Orally Administered Dipeptide Mimetic of the Brain-Derived Neurotrophic Factor

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