cyclic-gmp and Dementia--Vascular

A pathological glia activation, stimulated by inflammatory proteins, beta-amyloid, or brain ischemia, is discussed as a common pathogenic factor for progressive nerve cell damage in vascular and Alzheimer dementia. A critical point seems to be reached, if the cytokine-controlled microglial upregulation causes a secondary activation of astrocytes which loose the negative feedback control, are forced to give up their physiological buffering function, and may add to neuronal damage by the release of nitric oxide (NO) and by promoting toxic beta-amyloid formation. A strengthening of the cyclic adenosine-5',3'-monophosphate (cAMP) signaling exerted a differential inhibition of the stimulatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) released from cultured rat microglia, but maintained the negative feedback signal IL-6; cAMP inhibited also the release of free oxygen radicals (OR) but not of NO. Reinforcement of the NO-induced cyclic guanosine monophosphate (cGMP) increase by blockade of the phosphodiesterase (PDE) subtype-5 with propentofylline counterbalanced the toxic NO action that causes with OR neuronal damage by peroxynitrate formation. In rat cultured astrocytes, a prolonged cAMP elevation favored cell differentiation, the expression of a mature ion channel patter, and an improvement of the extracellular glutamate uptake. Cyclic AMP signaling could be strengthened by PDE blockade and by raising extracellular adenosine, which stimulates A2 receptor-mediated cAMP synthesis. Via an A1 receptor-mediated effect, elevated adenosine was found to overcome a deficient intracellular calcium mobilization resulting from an impaired muscarinic signaling at pathologically decreased acetylcholine concentrations. We suggest that pharmaca, which elevate extracellular adenosine and/or block the degradation of cyclic nucleotides, may be used to counteract glia-related neuronal damage in dementing processes.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Cyclic AMP; Cyclic GMP; Dementia, Vascular; Humans; Inflammation; Microglia; Models, Neurological; Neuroglia; Rats; Signal Transduction

Vascular dementia (VaD) is the second most common form of senile dementia, embraces memory deficits, neuroinflammation, executive function damage, mood and behavioral changes and abnormal cerebral blood flow. The purpose of the study was to explore the therapeutic potential of betulinic acid in bilateral common carotid artery occlusion (BCCAO) induced VaD in experimental rats. VaD was induced by BCCAO in rats and betulinic acid (10 and 15 mg/kg/day po) was administered 1 week after surgery. The cerebral blood pressure of the animal was recorded before and after the treatment using Laser Doppler flow meter. Object recognition task for non-spatial, Morris water maze for spatial and locomotor activity was performed to evaluate behavioral changes in rats. At the end of the study, animals were decapitated and hippocampus was separated to perform biochemical, neuroinflammatory and second messengers cAMP/cGMP analysis. Histology was done to study the brain pathophysiology. BCCAO surgery was able to significantly impaired memory in rats as observed behavioral and biochemical parameters. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA was able to re-establish cerebral blood flow, restore behavioral parameters and showed significant improvements in the as cAMP,cGMP and BDNF levels, restrain the oxidative stress and inflammatory parameters. In histopathology, betulinic acid treated groups showed a decrease in microgliosis and less pathological abnormalities comparable to diseased rat's brain. The observed effect might be attributed to the neuroprotective potential of betulinic acid and its ability to restore cognitive impairment and hippocampal neurochemistry in VaD.

Topics: Acetylcholinesterase; Animals; Betulinic Acid; Brain-Derived Neurotrophic Factor; Carotid Artery, Common; Cerebrovascular Circulation; Cyclic AMP; Cyclic GMP; Cytokines; Dementia, Vascular; Hippocampus; Locomotion; Male; Maze Learning; Memory Disorders; Oxidative Stress; Pentacyclic Triterpenes; Phosphodiesterase Inhibitors; Rats; Rats, Wistar; Triterpenes