Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well accepted that adverse life events occurring early in development may alter the correct program of brain maturation leading to enhanced vulnerability to neuropsychiatric disorders. It has recently been demonstrated that prenatal exposure to the cannabinoid receptor 1 agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2) produces memory deficit in adulthood, an effect associated with a reduced functionality of the glutamatergic system. The aim of our study was to identify molecular changes produced by prenatal exposure to WIN 55,212-2 that might contribute to late disruption in synaptic plasticity and cognition. For this purpose, WIN 55,212-2 was injected in pregnant wistar rats from gestation day 5 to 20 and a detailed analysis of the levels of the neurotrophin brain-derived neurotrophic factor (BDNF) as well as of the signaling molecules extracellular signal-regulated kinase (ERK)1/2 and alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) was carried out in adult offspring. We found that exposure to WIN 55,212-2 significantly reduced BDNF levels in hippocampus and frontal cortex. This effect was associated with decreased activation of pathways linked to neurotrophin and glutamate receptor signaling. In particular, prenatal cannabinoid treatment reduced the phosphorylated levels of ERK1/2 in selected subcellular compartments of hippocampus, frontal and prefrontal cortex, whereas no changes were observed in the total levels of these proteins. Furthermore, a robust reduction of total and phospho-alpha-CaMKII was found in the hippocampus of rats prenatally exposed to WIN 55,212-2. In summary, the present data suggest that deficits of BDNF levels and signaling through ERK1/2 and alpha-CaMKII might contribute to cognitive and neuroplastic defects associated with prenatal exposure to cannabinoids.
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PMID:Long-term reduction of brain-derived neurotrophic factor levels and signaling impairment following prenatal treatment with the cannabinoid receptor 1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1- naphthalenylmethanone. 1755 98

Recently, synthetic cannabinoids have been sprayed onto plant material, which is subsequently packaged and sold as "Spice" or "K2" to mimic the effects of marijuana. A recent report identified several synthetic additives in samples of "Spice/K2", including JWH-081, a synthetic ligand for the cannabinoid receptor 1 (CB1). The deleterious effects of JWH-081 on brain function are not known, particularly on CB1 signaling, synaptic plasticity, learning and memory. Here, we evaluated the effects of JWH-081 on pCaMKIV, pCREB, and pERK1/2 signaling events followed by long-term potentiation (LTP), hippocampal-dependent learning and memory tasks using CB1 receptor wild-type (WT) and knockout (KO) mice. Acute administration of JWH-081 impaired CaMKIV phosphorylation in a dose-dependent manner, whereas inhibition of CREB phosphorylation in CB1 receptor WT mice was observed only at higher dose of JWH-081 (1.25 mg/kg). JWH-081 at higher dose impaired CaMKIV and CREB phosphorylation in a time-dependent manner in CB1 receptor WT mice but not in KO mice and failed to alter ERK1/2 phosphorylation. In addition, SR treated or CB1 receptor KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio compared with vehicle or WT littermates. In hippocampal slices, JWH-081 impaired LTP in CB1 receptor WT but not in KO littermates. Furthermore, JWH-081 at higher dose impaired object recognition, spontaneous alternation and spatial memory on the Y-maze in CB1 receptor WT mice but not in KO mice. Collectively our findings suggest that deleterious effects of JWH-081 on hippocampal function involves CB1 receptor mediated impairments in CaMKIV and CREB phosphorylation, LTP, learning and memory in mice.
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PMID:CB1 receptor-mediated signaling underlies the hippocampal synaptic, learning, and memory deficits following treatment with JWH-081, a new component of spice/K2 preparations. 2412 67