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Insulin Resistance as a Risk Factor for Alzheimer's Disease
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Miren Ettcheto, Amanda Cano, Elena Sanchez-Lopez, Carme Auladell, Jaume Folch, Antoni Camins
In this context, Grillo and colleagues performed a preclinical study in a selective IR model of the rat using a lentiviral vector expressing an insulin receptor antisense sequence (42). They demonstrated that the generation of specific IR in the hippocampus affected the synaptic plasticity in this area by regulating the expression and trafficking of the glutamate receptor. Specifically, this study showed that IR decreased the phosphorylation of the serine 845 residue of the glutamate receptor 1 (GluA1) and the expression of glutamate ionotropic receptor N-Methyl D-Aspartate (NMDA) type subunit 2B (GluN2B), which are directly involved in long term potentiation (LTP) (42, 43). In line with these results, it has been reported that insulin administration promotes dendritic spine formation in primary cultures of rat hippocampal neurons and improves synaptic transmission through NMDA receptor (glutamatergic transmission) in the hippocampus, modulating the surface expression of these receptors and stimulating the phosphorylation of GluN2A and GluN2B subunits (36, 44).
Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Epileptic encephalopathies associated with chorea:28GNAO1 mutations.SCN1A-related phenotypic.FOXG1 mutations.SCN8A mutations.SCN2A-related disorders.UBA5 mutations.DNM1 mutations.FRRS1L mutations.GRIN1/GRIN2B/GRIN2D mutations.
Phytochemical, Pharmacological and Therapeutic Profile of Bacopa monnieri
Published in Dilip Ghosh, Pulok K. Mukherjee, Natural Medicines, 2019
Muhammad Shahid, Fazal Subhan, Nazar Ul Islam, Ihsan Ullah, Javaid Alam, Nisar Ahmad, Gowhar Ali
Bacopa monnieri is effective for both anterograde and retrograde amnesia (Saraf et al. 2011). The anti-amnesic effect of Bacopa monnieri is mediated by the gamma aminobutyric acid-benzodiazepine pathway (Prabhakar et al. 2008) or by improving the release of nitric oxide (Saraf et al. 2009; Anand et al. 2010), thereby affecting long-term potentiation, which is the biological mechanism of learning and memory that produces amnesia. The anti-amnesic effect of Bacopa monnieri depends on the type of amnesic agent used with the alleviation of superoxide dismutase activity (Prabhakar et al. 2011), suppression of mitogen activated protein kinase, phosphorylated CREB, inducible nitric oxide synthase and upregulation of nitrite (Saraf et al. 2008) playing a dominant role in reversing amnesia induced by diazepam. Similarly, Bacopa monnieri reverses scopolamine-induced amnesia by improving calmodulin and partially attenuating protein kinase-C and phosphorylated-CREB (Saraf et al. 2010), and decreasing the acetylcholinesterase activity and upregulating the expression of NMDA receptor subunit GluN2B in the prefrontal cortex and hippocampus (Rai et al. 2015). Moreover, Bacopa monnieri – besides reducing the cognitive deficit side effect of phenytoin (Vohora et al. 2000) – also reduces D-galactose–induced contextual associative learning deficit by enhancing antioxidant enzyme activities and stabilising neurotransmitter release and synaptic proteins levels (Dulcy and Rajan 2009).
Change in gene expression levels of GABA, glutamate and neurosteroid pathways due to acoustic trauma in the cochlea
Published in Journal of Neurogenetics, 2021
Meltem Cerrah Gunes, Murat Salih Gunes, Alperen Vural, Fatma Aybuga, Arslan Bayram, Keziban Korkmaz Bayram, Mehmet Ilhan Sahin, Muhammet Ensar Dogan, Sevda Yesim Ozdemir, Yusuf Ozkul
Grin2b (Nmdar2b) encodes N-methyl-D-aspartate receptor channel subunit 2b (Matta, Ashby, Sanz-Clemente, Roche, & Isaac, 2011) and acts as an agonist binding site for glutamate. Activation of the NMDA receptor containing NR2B increase excitotoxicity and neuronal apoptosis(Y. Liu et al., 2007). None of the rats exhibited tinnitus behaviour when the NMDA antagonist ifenprodil was applied locally to the cochlea within 4 days following the noise. However, 3 out of 8 rats exhibited tinnitus behaviour when ifenprodil applied after 8 days post-AT (Guitton & Dudai, 2007). In our study, the expressions of Grin2b was increased in Post-AT(1) group when compared to the control group, but it wasn't statistically significant and no significant change was detected between control and Post-AT(15). However, there was a significant decrease in Post-AT(15) group when compared to Post-AT(1) group. These results support that NMDA receptors can be effective in the pathophysiology of the acute phase of acoustic trauma (Guitton & Dudai, 2007), but we may not have detected the maximum peak of this increase. Additionally, the response to trauma may vary depending on the type of trauma, the experimental animal used, the tissue, and the receptor subunit differences (Kumar, Zou, Yuan, Long, & Yang, 2002; Schumann, Alexandrovich, Biegon, & Yaka, 2008).
Hydrogen sulfide: a target to modulate oxidative stress and neuroplasticity for the treatment of pathological anxiety
Published in Expert Review of Neurotherapeutics, 2020
Mary Chen, Caroline Pritchard, Diandra Fortune, Priyadurga Kodi, Marco Grados
The NMDA receptor (NMDAR) is an ionotropic glutamate receptor found in the membranes of neurons with a well-known role in LTP, activated when bound by glutamate and glycine, and allowing Ca2+ entry into the cell. NMDA receptor activation, in turn, is facilitated by H2S in a concentration-dependent manner. In contrast, H2S does not appear to affect the function of AMPA receptors, at least directly [25]. The LTP-facilitating effect of H2S on NMDA receptors also depends on the generation of the signaling messenger molecule cAMP, a second messenger critical in neuroplasticity transduction signaling systems [71]. Finally, NMDA activation requires phosphorylation at specific sites, notably of the NMDA component GRIN2B, leading to the activation of kinases, such as the exclusively brain-expressed protein kinase PKC-γ, which interacts with H2S in neuronal pathways. PKC-γ, a key kinase in neuroplasticity [72], and H2S, are now known to act together in the induction of central pain mechanism responses. In this model of chronic pain (pancreatitis in male adult Sprague-Dawley rats), the chronic stress response induces CBS production, resulting in increased H2S formation which, in turn, triggers phosphorylation of NMDA (p-GRIN2B expression) via upregulation of PKC-γ in CNS nuclei [73].
Lost in translation? A critical look at the role that animal models of obsessive compulsive disorder play in current drug discovery strategies
Published in Expert Opinion on Drug Discovery, 2018
Kurt Leroy Hoffman, Hugo Cano-Ramírez
If not based on information from using animal models to screen potential anti-compulsive drugs, how were the novel OCD drug candidates that are currently being investigated identified? Judging from the published literature, many were identified based on (1) clinical observations in the form of case studies or small open-label trials and (2) neurobiological models for OCD symptomatology, which were in turn derived from neuroimaging studies of human subjects, along with basic neurobiological research using nonhuman animal subjects [8–12]. For example, the first case study to report that memantine reduced OCD symptoms [53], published in 2005, did not cite studies involving animal models of OCD as a rationale for testing this drug in the clinic, even though findings from the D1CT transgenic mouse model [32] and the deer mouse spontaneous stereotypy model [33] had associated alterations in striatal glutamate with compulsive-like behavior. Rather, this case study cited the then recent association of certain polymorphisms of the GRIN2B gene with familial OCD [54], a study which in turn was motivated largely by clinical imaging studies showing alterations in striatal glutamate in OCD [30,31].