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Preclinical Antidepressant-Like Effects of Terpenes, Polyphenolics, and Other Non-Flavonoid Phytochemicals
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Chronic administration of macranthol restored preference for sucrose and reduced immobility time in the forced swim and tail suspension tests in mice that had been subjected to chronic unpredictable stress. It also reduced serum levels of corticosterone. Neurochemically, it maintained levels of serotonin in the frontal cortex and hippocampus. Chronic, though not acute administration of macranthol, also increased levels of BDNF in stressed mice.125 Indeed, in a follow-up study, the antidepressant-like effects of macranthol were blocked by the TrkB antagonist K252a. It was concluded that the antidepressant effect was due to activation of BDNF and TrkB and downstream stimulation of the PI3K/Akt-Bcl-2/caspase-3 signaling pathway.126
Nerve Growth Factor and Its Receptor System in Rheumatologic Diseases and Pain Management
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Smriti K. Raychaudhuri, Siba P. Raychaudhuri
Systemic use of K252a has been restricted due to its toxicities. Pincelli and Pignattim have extended our observations and are currently developing a topical preparation of K252a for psoriasis [88]. Many pharmaceutical companies are also in search of an anti-NGF therapy for psoriasis, autoimmune arthritis, and pain control. Shelton et al. from Rinat Neuroscience Corp. have observed the efficacy of anti-NGF antibody in a rat model of autoimmune arthritis [89]. Rats, after development of severe arthritis, received either of these two types of anti-NGF antibody: muMab 911 (a mouse antibody to NGF, i.v., days 14 and 19) or RI 624 (a humanized version of this antibody, i.v., days 14 and 19). Saline and indomethacin (3 mg/kg, p.o.) were the control groups. Treatment with anti-NGF had significant improvement of pain, and the analgesic effect was achieved within 24 h of therapy. Pain relief from anti-NGF therapy was comparable to or better than that of indomethacin.
Phosphoinositide Metabolism
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
A number of exogenous inhibitors of protein kinase C have been described but many of them may be unspecific and their action mechanism is frequently unknown. Staurosporine, an alkaloid purified from Streptomyces actuosus, is a potent inhibitor of protein kinase C, but it may also inhibit protein kinase A and tyrosine kinases at similar concentrations. The 7-hydroxy derivative of staurosporine, UCN-10, is a more selective and potent inhibitor of protein kinase C activity. Calphostin C, isolated from the fungus Cladosporium cladosporioides, is potent and more selective for protein kinase C due to its interaction with the regulatory domain of the enzyme.211 The protein K252a, isolated from a microbe (Nocardipsis sp.), inhibits protein kinase C activity in vivo by competing with ATP.212 The application of protein kinase C inhibitors may contribute to the elucidation of the precise functions of the enzyme in normal and tumor cells. The discovery that sangivamycin, a purine nucleotide analog with antitumor activity, is an inhibitor of protein kinase C could open new possibilities for the design of antitumor compounds.213 However, protein kinase C inhibitors may have toxic effects on a number of metabolic processes. The study of mutant cell clones that lack functional protein kinase C molecules may give clues to make clearer the role of the enzyme in physiological processes occurring in different types of cells.214
Mulberry fruit improves memory in scopolamine-treated mice: role of cholinergic function, antioxidant system, and TrkB/Akt signaling
Published in Nutritional Neuroscience, 2021
Suk Kyung Shin, Jae-Myung Yoo, Fu Yi Li, Seong Yeon Baek, Mee Ree Kim
DMEM, 1× PBS and 1× TBS were purchased from Welgene, Inc. (Gyeongsan, Gyeongbuk, Korea). FBS, 0.25% trypsin-EDTA, antibiotics, and 2,7-dichlorofluorescein diacetate (DCFDA) were obtained from Invitrogen (Carlsbad, CA, USA). K252a (a TrkB inhibitor) and MK-2206 (a specific Akt inhibitor) were purchased from Cayman Chemical Company (Ann Arbor, MI, USA). EZ-Cytox cell viability assay kit was obtained from Daeil Lab (Seoul, Korea). Specific antibodies against apoptosis-inducing factor (AIF), Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), phospho-Akt, phospho-TrkB, phospho-cAMP response element-binding protein (CREB), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), NF-E2-related factor-2 (Nrf2), and β-actin as well as a horseradish peroxidase-conjugated IgG secondary antibody were purchased from Cell Signaling Technology (Beverly, MA, USA). Specific antibodies against cytochrome c and NAD(P)H quinine oxidoreductase-1 (NQO-1) were obtained from Abcam, Inc. (Cambridge, UK). A specific antibody against brain-derived neurotrophic factor (BDNF) was purchased from Santa Cruz Biotechnology, Inc. (Dallas, TX, USA). Protease and phosphatase inhibitor cocktails were purchased from Roche Diagnostics (Indianapolis, IN, USA). BCA protein assay kit was purchased from iNtRON Biotechnology, Inc. (Seongnam, Korea). Radioimmunoprecipitation assay (RIPA) buffer, Muse Annexin V & Dead Cell Assay Kit, and Muse Mitopotential Assay Kit were obtained from Merck Millipore, Inc. (Darmstadt, Germany). All other chemicals were of analytical grade and obtained from Sigma-Aldrich (St Louis, MO, USA).
A Small Molecule TrkB Neurotrophin Receptor Partial Agonist as Possible Treatment for Experimental Nonarteritic Anterior Ischemic Optic Neuropathy
Published in Current Eye Research, 2018
Mohammad Ali Shariati, Varun Kumar, Tao Yang, Chandrani Chakraborty, Ben Anthony Barres, Frank Michael Longo, Yaping Joyce Liao
Among all LM22A compounds, LM22A-4 has been particularly studied due to its selectivity11,18 for TrkB receptor. Massa et al. demonstrated that LM22A-4 and BDNF compete for the TrkB receptor binding without any detectable effects on TrkA and TrkC, or P75NTR.11 Massa et al. showed that LM22A-4’s specific affinity for TrkB and the absence of P75NTR binding make LM22A-4 distinct from a BDNF mimetic that would have evoked a full range of BDNF-related activities.11 LM22A-4 can penetrate the blood-brain barrier in sufficient amount and activates TrkB to initiate cytoplasmic MAPK signaling pathway.11 Co-administration of TrkB and BDNF leads to a 10%–20% reduction in BDNF activity and no additive effect on survival of hippocampal neurons, consistent with competition for the same TrkB receptor.11 Application of K252a, a known Trk inhibitor, or an inhibitory antibody that binds to the extracellular domain of TrkB lead to a reduction in neurotrophic activity or increased TUNEL-positive cells of BDNF and LM22A-4.11
Sitagliptin rescues memory deficits in Parkinsonian rats via upregulating BDNF to prevent neuron and dendritic spine loss
Published in Neurological Research, 2018
Jing Li, Shuhu Zhang, Chenye Li, Mei Li, Lan Ma
The completion of the above tests basically determined the effect of sitagliptin on Parkinson’s disease learning and memory function. Whether the change in BDNF content after sitagliptin administration had an effect on Parkinson’s disease remained to be further confirmed. K252a was used for the confirmation. K252a is known as a blocker of Trk receptors that could block the biological effect of BDNF [23]. As shown in Figure 5(a), from the third training day to the fifth training day in MWM test, the latency time in 6-OHDA + sitagliptin + vehicle group was significantly decreased compared with 6-OHDA + vehicle group, which indicated that sitagliptin could rescue the defect caused by 6-OHDA. However, after adding K252a, latency time in 6-OHDA + sitagliptin + K252a group was increased. In the probe test on the sixth day and the passive avoidance test, the latency time in 6-OHDA + Sitagliptin group was increased compared with 6-OHDA + vehicle group, while the addition of K252a decreased this effect [Figure 5(b), F (2, 15) = 98.272, P < 0.01; Figure 5(c), F (2, 15) = 98.845, P < 0.01]. These results verified that sitagliptin can improve memory function in PD rats, which was modulated by upregulating BDNF.