am-404 and Hyperglycemia

Hyperglycemia accelerates the progression of Alzheimer's disease (AD), and GSK3β plays a potential link between AD and hyperglycemia. Therefore, a direct or indirect GSK3β inhibition may have potential to delay the progression of AD. Our previous biochemical assay identified AM404 as a GSK3β inhibitor at high dose (IC50 = 5.353 μM); however, other study suggests that AM404 impaired synaptic plasticity of hippocampus at high dose (10 mg/kg; i.p.). Therefore, the dose and duration of treatment are crucial for the effects of AM404.. The effects and molecular mechanisms of AM404 at low dose were evaluated from in vitro to in vivo models.. AM404 (0.1-0.5 μM) was tested on tau hyperphosphorylated mouse hippocampal primary cultures treated with Wortmannin (WT) and GF109203X (GFX). Hyperglycemic triple transgenic AD (3×Tg-AD) mice at 6 months old were intraperitoneally injected with AM404 (0.25 mg/kg) for 4 weeks. The spatial learning and memory of mice were measured using the Morris water maze. Mouse brain and serum samples were collected for pathological analyses.. AM404 (0.5 μM) exhibited significantly augmented neuroprotection toward tau hyperphosphorylation in primary cultures. The chronic systemic administration of AM404 (0.25 mg/kg) attenuated cognitive deficits in hyperglycemic 3×Tg-AD mice. Moreover, chronic low dose of AM404 significantly attenuated Aβ production, tau protein phosphorylation, and inflammation associated with an increase of pS473Akt and pS9-GSK3β. Therefore, AM404 at low dose, not only increased neuroprotection, but also ameliorated cognitive deficit, could be partly by regulating the Akt/GSK3β signaling, which may contribute to downregulation of Aβ, tau hyperphosphorylation, and inflammation in hyperglycemic 3×Tg-AD mice.. These results highlight that chronic administration of AM404 at low dose may be through the Akt/GSK3β pathway to ameliorate the impairment in hyperglycemic 3×Tg-AD mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Arachidonic Acids; Cognitive Dysfunction; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glycogen Synthase Kinase 3 beta; Hippocampus; Humans; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Pregnancy; tau Proteins

1. Diabetic rats display increased pain responses following injection of formalin into the paw, suggesting the presence of hyperalgesia. In the present study, we investigated the efficacy of the systemic administration of the endocannabinoid transport inhibitors UCM707 and AM404 (1, 10 and 50 mg/kg, i.p.) on hyperalgesia during the formalin test in streptozocin (STZ)-induced diabetic rats. 2. Nociceptive testing was performed in male adult Wistar rats 4 weeks after the onset of hyperglycaemia. At the end of the experiment, all rats were weighed and then underwent plasma glucose measurements. 3. Diabetes caused significant hyperalgesia during both phases of the formalin test. At 10 and 50 mg/kg, both UCM707 and AM404 reversed chemical hyperalgesia in diabetic rats. UCM707 (10 and 50 mg/kg) caused less intensive nociceptive behaviour during both phases of the test, whereas AM404 (10 and 50 mg/kg) only affected pain scores during Phase 1 of the formalin test. At 1 mg, neither drug had any effect on pain behaviour in control and diabetic groups compared with their respective controls. Neither UCM707 nor AM404 had any effect on bodyweight or plasma glucose levels of treated compared with non-treated rats at any of the doses tested. 4. The results of the present study indicate that systemic administration of UCM707 and AM404 is effective in ameliorating chemical hyperalgesia in STZ-diabetic rats. Thus, endocannabinoid transport inhibitors may have potential in the treatment of painful diabetic neuropathy.

Topics: Animals; Arachidonic Acids; Blood Glucose; Body Weight; Cannabinoid Receptor Modulators; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Endocannabinoids; Furans; Hyperalgesia; Hyperglycemia; Male; Pain; Pain Measurement; Plasma Membrane Neurotransmitter Transport Proteins; Polyunsaturated Alkamides; Rats