Gabapentin and (S)-pregabalin decrease intracellular d-serine concentrations in PC-12 cells

Singh, Nagendra; Paul, Rajib; Torjman, Marc C.; Wainer, Irving W.

doi:10.1016/j.neulet.2012.12.024

Cited by 14 publications

(15 citation statements)

References 32 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, previous studies in our laboratory have indicated that the incubation of PC-12 cells with increasing concentrations of methyllycaconitine or ( R,S )-dehydroxynorketamine decreases the intracellular concentration of the NMDAR co-agonist D-serine, a product of SR-mediated racemization of L-serine, despite higher expression of m-SR 14 . A similar decrease in intracellular D-serine concentrations was observed after incubation of PC-12 cells with the voltage-gated calcium channel α 2 δ inhibitors gabapentin and (S)-pregabalin 21 , which are used in the treatment of neuropathic pain, without impacting on m-SR protein level. The inhibition of SR activity has also been associated with a decrease in NMDAR activity, and SR inhibitors are being explored for use in the treatment of some CNS disorders 22,23 .…”

Section: Discussionsupporting

confidence: 58%

(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function

et al. 2014

Self Cite

View full text Add to dashboard Cite

Background Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown. Methods Rats (n = 3/time point) were given (R,S)-ketamine, (R,S)-norketamine and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 minutes. PC-12 pheochromocytoma cells (n = 3/experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined. Results The phosphorylation of mTOR and its downstream targets was significantly increased in rat pre-frontal cortex tissue by more than ~2.5-, ~25- and ~2-fold, respectively, in response to a 60-min post-administration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (p<0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05nM (2S,6S)-hydroxynorketamine, 10nM (R,S)-norketamine and 1000nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor. Conclusions The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by sub-anesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.

show abstract

Section: Discussionsupporting

confidence: 58%

(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…This inhibition lowers intracellular Ca 2+ , which, in turn, reduces the magnitude of Ca 2+ -activated SR and consequently the intracellular D-Ser concentrations. A similar reduction in intracellular D-Ser concentration was observed after incubation with gabapentin and ( S )-pregabalin, which reduce intracellular Ca 2+ concentrations via inhibition of the α 2 -δ subunit of voltage-gated calcium channels [24]. Based upon these observations and the recent report identifying a relationship between reduced D-Ser concentrations and attenuated NMDA receptor activity in rat and mouse models [22], it is reasonable to assume that a ( 2S,6S )-HNK-associated reduction in D-Ser production should also result in reduced NMDA receptor activation and associated neurotoxicity, synaptic death and depression.…”

mentioning

confidence: 68%

What is hydroxynorketamine and what can it bring to neurotherapeutics?

Singh

Zarate

Moaddel

et al. 2014

Expert Review of Neurotherapeutics

View full text Add to dashboard Cite

(R,S)-Ketamine was initially developed as an anesthetic agent and its pharmacological properties were determined on the basis of this clinical use. However, pharmacological studies in rat led to the development of the ‘Ketamine Paradigm’, whereby (R,S)-ketamine and its N-demethylated metabolite (R,S)-norketamine were deemed the active compounds whereas the other ketamine metabolites were considered inactive. Recent in vivo and in vitro studies with (2S,6S)-hydroxynorketamine, a previously identified ‘inactive’ metabolite, have demonstrated that this compound is an active and selective inhibitor of the α7 subtype of the nicotinic acetylcholine receptor and that this activity contributes to the pharmacological responses associated with the antidepressant activity of (R,S)-ketamine. Thus, it appears that it is necessary to reassess the ‘Ketamine Paradigm’ in regards to the use of sub-anesthetic doses of (R,S)-ketamine in the treatment of treatment-resistant depression.

show abstract

“…PC-12 cells were utilized here because they serve as a relevant in vitro model system for primary neuronal cells (Greene and Tischler 1976; Vignali et al 1996). They have been widely used to study voltage-gated Ca 2+ channels (Singh et al 2013; Zhang et al 2012) and effects of Mn 2+ exposure on these cells (Kwik-Uribe et al 2003; Reaney et al 2002; Zheng and Zhao 2001). Following withdrawal of doxycycline (Dox) from the medium, PC-12 cells were differentiated with nerve growth factor (NGF, R&D Systems 1156-NG/CF).…”

Section: Methodsmentioning

confidence: 99%

Improved Visualization of Neuronal Injury Following Glial Activation by Manganese Enhanced MRI

Bade

Zhou

Epstein

et al. 2013

J Neuroimmune Pharmacol

View full text Add to dashboard Cite

Research directed at anatomical, integrative and functional activities of the central nervous system (CNS) can be realized through bioimaging. A wealth of data now demonstrates the utility of magnetic resonance imaging (MRI) towards unraveling complex neural connectivity operative in health and disease. A means to improve MRI sensitivity is through contrast agents and notably manganese (Mn2+). The Mn2+ ions enter neurons through voltage-gated calcium channels and unlike other contrast agents such as gadolinium, iron oxide, iron platinum and imaging proteins, provide unique insights into brain physiology. Nonetheless, a critical question that remains is the brain target cells serving as sources for the signal of Mn2+ enhanced MRI (MEMRI). To this end, we investigated MEMRI’s abilities to detect glial (astrocyte and microglia) and neuronal activation signals following treatment with known inflammatory inducing agents. The idea is to distinguish between gliosis (glial activation) and neuronal injury for the MEMRI signal and as such use the agent as a marker for neural activity in inflammatory and degenerative disease. We now demonstrate that glial inflammation facilitates Mn2+ neuronal ion uptake. Glial Mn2+ content was not linked to its activation. MEMRI performed on mice injected intracranially with lipopolysaccharide was associated with increased neuronal activity. These results support the notion that MEMRI reflects neuronal excitotoxicity and impairment that can occur through a range of insults including neuroinflammation. We conclude that the MEMRI signal enhancement is induced by inflammation stimulating neuronal Mn2+ uptake.

show abstract

Gabapentin and (S)-pregabalin decrease intracellular d-serine concentrations in PC-12 cells

Cited by 14 publications

References 32 publications

(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function

(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function

What is hydroxynorketamine and what can it bring to neurotherapeutics?

Improved Visualization of Neuronal Injury Following Glial Activation by Manganese Enhanced MRI

Contact Info

Product

Resources

About