Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice

Jeon, Se Jin; Kim, Eunji; Lee, Jin Su; Oh, Hee Kyong; Zhang, Jiabao; Kwon, Yubeen; Jang, Dae Sik; Ryu, Jong Hoon

doi:10.1016/j.neuropharm.2017.09.014

Cited by 29 publications

(16 citation statements)

References 64 publications

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“…Unfortunately, the anatomy of naked mole rats, and specifically the location of large muscle masses on the top of the cranium, which are critical for eating, digging, and other social functions within the colony, makes stereotaxic implantation of permanent cannulas that target the respiratory brainstem detrimental to the health and sociability of this species. However, intraperitoneal injections of these same pharmacological agents have been used previously in numerous studies in mice and rats to evaluate a wide variety of physiological and behavioral responses (for example: Velisek et al, 1995; Mead and Stephens, 1999; Berrino et al, 2003; Murschall and Hauber, 2005; Reid and Powell, 2005; McGuire et al, 2008; Jeon et al, 2017; Xiang et al, 2018). This large body of literature in which these drugs impacted physiological function following intraperitoneal injection (as in our study) indicates that these agents successfully cross the blood brain barrier to interact with AMPARs and NMDARs, which are not found outside of the CNS.…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic Receptors Modulate Normoxic but Not Hypoxic Ventilation and Metabolism in Naked Mole Rats

et al. 2019

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Naked mole rats ( Heterocephalus glaber ) are among the most hypoxia-tolerant mammals, but their physiological responses to acute and chronic sustained hypoxia (CSH), and the molecular underpinnings of these responses, are poorly understood. In the present study we evaluated the acute hypoxic ventilatory response and the occurrence of ventilatory acclimatization to hypoxia following CSH exposure (8–10 days in 8% O 2 ) of naked mole rats. We also investigated the role of excitatory glutamatergic signaling in the control of ventilation and metabolism in these conditions. Animals acclimated to normoxia (control) or CSH and then exposed to acute hypoxia (7% O 2 for 1 h) exhibited elevated tidal volume (V T ), but decreased breathing frequency (f R ). As a result, total ventilation ( E ) remained unchanged. Conversely, V T was lower in CSH animals relative to controls, suggesting that there is ventilatory plasticity following acclimatization to chronic hypoxia. Both control and CSH-acclimated naked mole rats exhibited similar 60–65% decreases in O 2 consumption rate during acute hypoxia, and as a result their air convection requirement (ACR) increased ∼2.4 to 3-fold. Glutamatergic receptor inhibition decreased f R , E , and the rate of O 2 consumption in normoxia but did not alter these ventilatory or metabolic responses to acute hypoxia in either the control or CSH groups. Taken together, these findings indicate that ventilatory acclimatization to hypoxia is atypical in naked mole rats, and glutamatergic signaling is not involved in their hypoxic ventilatory or metabolic responses to acute or chronic hypoxia.

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Section: Discussionmentioning

confidence: 99%

Glutamatergic Receptors Modulate Normoxic but Not Hypoxic Ventilation and Metabolism in Naked Mole Rats

et al. 2019

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“…It has been well-established that NMDAR play a key role in the etiology and pharmacological treatments of schizophrenia ( Gilmour et al, 2012 ; Jadi et al, 2016 ; Dauvermann et al, 2017 ; Jeon et al, 2017 ). For instance, a considerable amount of research has demonstrated that NMDAR antagonists mimic psychosis-relevant behaviors and deficits in sensory gating ( Jeon et al, 2017 ; Oh et al, 2017 ). Based on this hypothesis, the current study evaluated the involvement of NMDAR subunits in the symptoms of schizophrenia in mice induced by the repeated administration of the NMDAR antagonist MK-801.…”

Section: Discussionmentioning

confidence: 99%

GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1

Zhou

Wang

et al. 2018

Front. Mol. Neurosci.

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Background: Evidence supports that the hypofunction of N-methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N-Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice.Methods: The effect of GLYX-13 was tested by observing changes in locomotor activity, novel object recognition ability, and prepulse inhibition (PPI) induced by dizocilpine (known as MK-801) in mice. Lentivirus-mediated NR2B knockdown in the hippocampus was assessed to confirm the role of NR2B in GLYX-13 pathophysiology, using Western blots and immunohistochemistry.Results: The systemic administration of GLYX-13 (0.5 and 1 mg/kg, i.p.) ameliorates MK-801 (0.5 mg/kg, i.p.)-induced hyperlocomotion, deficits in memory, and PPI in mice. Additionally, GLYX-13 normalized the MK-801-induced alterations in signaling molecules, including NR2B and DISC1 in the hippocampus. Furthermore, we found that NR2B knockdown produced memory and PPI deficits without any changes in locomotor activity. Notably, DISC1 levels significantly decreased by NR2B knockdown. However, the effective dose of GLYX-13 did not alleviate the memory and PPI dysfunctions or downregulation of DISC1 induced by NR2B knockdown.Conclusion: Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and DISC1 in the hippocampus may account for the molecular mechanisms of GLYX-13.

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“…NMDAR plays a key role in the etiology and drug treatment of SZ (Lee and Zhou, 2019). Numerous studies have confirmed that NMDAR antagonists induce SZ-related behavior (Jeon et al, 2017). Meanwhile, our previous studies (Ding et al, 2017(Ding et al, , 2019 and other work (Seillier and Giuffrida, 2009;Jacklin et al, 2012;Karamihalev et al, 2014;Li et al, 2016) found cognition impairment and alterations in anatomical and neurochemical aspects in a mouse subchronic model of SZ induced by the intraperitoneal injection of MK-801 for 14 consecutive days.…”

Section: Discussionmentioning

confidence: 85%

G Protein-Coupled Estrogen Receptor 1 Knockout Deteriorates MK-801-Induced Learning and Memory Impairment in Mice

Zhang

Liu

et al. 2020

Front. Behav. Neurosci.

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The role of estrogen receptors in neuroprotection and cognition has been extensively studied in humans over the past 20 years. Recently, studies have shifted their focus to the use of selective estrogen receptor modulators in the treatment of mental illnesses in the central nervous system. We conducted this study to test the behavioral changes shown by G protein-coupled estrogen receptor 1 knockout (GPER1 KO) and wild-type (WT) mice with MK-801-induced schizophrenia (SZ). GPER1 KO and WT mice received intraperitoneal injections of MK-801 for 14 continuous days. Behavioral, learning and memory, and social interaction changes were evaluated by using the IntelliCage system, open-field, three-chamber social interaction, and novel object recognition tests (NORT). The protein expression levels of the NR2B/CaMKII/CREB signaling pathway were tested via Western blot analysis. The KO SZ group was more likely to show impaired long-term learning and memory function than the WT SZ group. Learning and memory functions were also impaired in the KO Con group. MK-801 administration to the GPER1-KO and WT groups resulted in memory deficiencies and declining learning capabilities. GPER1 deficiency downregulated the expression levels of proteins related to the NR2B/CaMKII/CREB signaling pathway. Our study suggested that GPER1 played an important role in cognitive, learning, and memory functions in the MK-801-induced mouse model of SZ. The mechanism of this role might partially involve the downregulation of the proteins related to the NR2B/CaMKII/CREB signaling pathway. Further studies should focus on the effect of GPER1 on the pathogenesis of SZ in vivo and in vitro.

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Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice

Cited by 29 publications

References 64 publications

Glutamatergic Receptors Modulate Normoxic but Not Hypoxic Ventilation and Metabolism in Naked Mole Rats

Glutamatergic Receptors Modulate Normoxic but Not Hypoxic Ventilation and Metabolism in Naked Mole Rats

GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1

G Protein-Coupled Estrogen Receptor 1 Knockout Deteriorates MK-801-Induced Learning and Memory Impairment in Mice

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