Pentobarbital and other anesthetic agents induce opposite regulations of MAP kinases p-MEK and p-ERK, and upregulate p-FADD/FADD neuroplastic index in brain during hypnotic states in mice.

Midazolam and ketamine-induced anesthesia were recently shown to induce a disruption of MEK/ERK sequential phosphorylation with parallel upregulation of p-FADD in the mouse brain. The present study was designed to assess whether other structurally diverse anesthetic agents (pentobarbital, ethanol, chloral hydrate, isoflurane) also impair brain p-MEK to p-ERK signal and increase p-FADD during the particular time course of 'sleep' in mice. Pentobarbital (50 mg/kg)-, ethanol (4000 mg/kg)-, chloral hydrate (400 mg/kg)-, and isoflurane (2% in O)-induced anesthesia (range: 24-60 min) were associated with unaltered or increased p-MEK1/2 (up to +155%) and decreased p-ERK1/2 (up to -60%) contents, revealing disruption of MEK to ERK activation in mouse brain cortex.

Ketamine-induced hypnosis and neuroplasticity in mice is associated with disrupted p-MEK/p-ERK sequential activation and sustained upregulation of survival p-FADD in brain cortex: Involvement of GABA receptor.

Ketamine (KET) is an antidepressant and hypnotic drug acting as an antagonist at excitatory NMDA glutamate receptors. The working hypothesis postulated that KET-induced sleep in mice results in dysregulation of mitogen-activated protein kinases (MAPK) MEK-ERK sequential phosphorylation and upregulation of survival p-FADD and other neuroplastic markers in brain. Low (5-15 mg/kg) and high (150 mg/kg) doses of KET on target proteins were assessed by Western immunoblot in mouse brain cortex.

A Biomarker to Differentiate between Primary and Cocaine-Induced Major Depression in Cocaine Use Disorder: The Role of Platelet IRAS/Nischarin (I-Imidazoline Receptor).

The association of cocaine use disorder (CUD) and comorbid major depressive disorder (MDD; CUD/MDD) is characterized by high prevalence and poor treatment outcomes. CUD/MDD may be primary (primary MDD) or cocaine-induced (CUD-induced MDD). Specific biomarkers are needed to improve diagnoses and therapeutic approaches in this dual pathology.

Regulation of cannabinoid CB receptor constitutive activity in vivo: repeated treatments with inverse agonists reverse the acute activation of JNK and associated apoptotic signaling in mouse brain.

Rationale: CB receptors express constitutive activity and inverse agonists regulate receptor basal activity, which might be involved in death mechanisms. This study assessed the effects of a selective CB agonist (JWH133) and different CB inverse agonists (AM630, JTE907, raloxifene) on death pathways in brain.

Objectives: The acute (JWH13) and the acute/chronic effects (AM630, JTE907, raloxifene) of CB ligands regulating pro-apoptotic c-Jun NH-terminal kinase (p-JNK/JNK ratio) and associated signaling of extrinsic (Fas receptor, Fas-Associated death domain protein, FADD) and intrinsic (Bax, cytochrome c) death pathways (nuclear poly (ADP-ribose) polymerase PARP) were investigated in mouse brain.

Disruption of brain MEK-ERK sequential phosphorylation and activation during midazolam-induced hypnosis in mice: Roles of GABA receptor, MEK1 inactivation, and phosphatase MKP-3.

Midazolam is a positive allosteric modulator at GABA receptor that induces a short hypnosis and neuroplasticity, in which the sequential phosphorylation of MEK1/2 and ERK1/2 was shown to play a role. This study investigated the parallel activation of p-MEK and p-ERK and regulatory mechanisms induced by midazolam through the stimulation of GABA receptors in the mouse brain. During the time course of midazolam (60mg/kg)-induced sleep in mice (lasting for about 2h) p-Ser217/221 MEK1/2 was increased (+146% to +258%) whereas, unexpectedly, p-Tyr204/Thr202 ERK1/2 was found decreased (-16% to -38%), revealing uncoupling of MEK to ERK signals in various brain regions.

The neuroplastic index p-FADD/FADD and phosphoprotein PEA-15, interacting at GABAA receptor, are upregulated in brain cortex during midazolam-induced hypnosis in mice.

Fas-associated death domain (FADD) adaptor is involved in the signaling of metabotropic G protein-coupled receptors, whose agonists stimulate its phosphoryaltion (p) increasing p-FADD/FADD ratio in brain. Whether FADD might also participate in the activation of dissimilar receptors such as the ligand-gated ion channels is not known. This study investigated the role of FADD and phosphoprotein-enriched in astrocytes of 15 kDa (PEA-15, a FADD partner) in the activation of γ-aminobutyric acid-A (GABAA) receptor, which mediates the hypnotic effect of midazolam.

Reduced platelet G protein-coupled receptor kinase 2 in major depressive disorder: antidepressant treatment-induced upregulation of GRK2 protein discriminates between responder and non-responder patients.

The homologous regulation of neurotransmitter receptors by G protein-coupled receptor kinases (GRKs) is important in the pathogenesis and treatment of major depressive disorder (MDD). Previous studies have reported that the basal status of GRK2 is different in brains (upregulation) and platelets (downregulation) of subjects with MDD. The principal aim of this study was to re-examine the status of platelet membrane GRK2 protein in patients with MDD, along with GRK3 (a close kinase homolog) and GRK5 (a kinase with different properties), before and after treatment with serotonin-selective reuptake inhibitor (SSRI) or serotonin noradrenaline reuptake inhibitor (SNRI) antidepressants.