Cannabinoid (CB) ligands have demonstrated neuroprotective properties. In this study we compared the effects of a diverse set of CB ligands against β amyloid-mediated neuronal toxicity and activated microglial-conditioned media-based neurotoxicity in vitro, and compared this with a capacity to directly alter β amyloid (Aβ) fibril or aggregate formation. Neuroblastoma (SH-SY5Y) cells were exposed to Aβ1-42 directly or microglial (BV-2 cells) conditioned media activated with lipopolysaccharide (LPS) in the presence of the CB1 receptor-selective agonist ACEA, CB2 receptor-selective agonist JWH-015, phytocannabinoids Δ(9)-THC and cannabidiol (CBD), the endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide or putative GPR18/GPR55 ligands O-1602 and abnormal-cannabidiol (Abn-CBD). TNF-α and nitrite production was measured in BV-2 cells to compare activation via LPS or albumin with Aβ1-42. Aβ1-42 evoked a concentration-dependent loss of cell viability in SH-SY5Y cells but negligible TNF-α and nitrite production in BV-2 cells compared to albumin or LPS. Both albumin and LPS-activated BV-2 conditioned media significantly reduced neuronal cell viability but were directly innocuous to SH-SY5Y cells. Of those CB ligands tested, only 2-AG and CBD were directly protective against Aβ-evoked SH-SY5Y cell viability, whereas JWH-015, THC, CBD, Abn-CBD and O-1602 all protected SH-SY5Y cells from BV-2 conditioned media activated via LPS. While CB ligands variably altered the morphology of Aβ fibrils and aggregates, there was no clear correlation between effects on Aβ morphology and neuroprotective actions. These findings indicate a neuroprotective action of CB ligands via actions at microglial and neuronal cells.

No abstract

No abstract

GABA(B)-receptor (GABA(B)R) agonists reduce transient lower esophageal sphincter relaxation (TLESR) and reflux episodes through an action on vagal pathways. In this study, we determined whether GABA(B)R are expressed on vagal afferent neurones and whether they modulate distension-evoked discharge of vagal afferents in the isolated stomach. Vagal mehanoreceptor activity was recorded following distensions of the isolated ferret proximal stomach before and after perfusion with the GABA(B)R-selective agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA). Retrograde labeling and immunohistochemistry were used to identify GABA(B)R located on vagal afferent neurones in the nodose ganglia. Vagal afferent fibers responded to isovolumetric gastric distension with an increase in discharge. The GABA(B)-receptor agonists baclofen (5 x 10(-5) M) and 3-APPiA (10(-6) to 10(-5) M) but not muscimol (GABA(A)-selective agonist: 1.3 x 10(-5) M) significantly decreased afferent distension-response curves. The effect of baclofen (5 x 10(-5) M) was reversed by the GABA(B)-receptor antagonist CGP 62349 (10(-5) M). Over 93% of retrogradely labeled gastric vagal afferents in the nodose ganglia expressed immunoreactivity for the GABA(B)R. GABA(B)R expressed on vagal afferent fibers directly inhibit gastric mechanosensory activity. This is likely a contributing mechanism to the efficacy of GABA(B)-receptor agonists in reducing TLESR and reflux episodes in vivo.