ABSTRACT
Amyloidß-protein (Aß) assembly into toxic fibrillar structures is seminal in development of senile plaques, the pathological hallmark of Alzheimer's disease. Blocking this process could have a therapeutic value. ß-sheet breaker peptides (ßSBP) decrease Aß fibrillogenesis and neurotoxicity by preventing or dissolving misfolded Aß aggregates. The present study investigated the effects of ßSBPs on Aß40-related neuropathology, memory impairment in 8-armed radial maze and expression of Aß40 in brain and serum. Aß40 was injected into amygdaloid nucleus followed 8 days later by octapeptideßSBPs 15-22, 16-23 and 17-24. Aß40 was detected not only in amygdala, but also in serum. Aß40 induced cellular changes in amygdala and additionally in hippocampus. Aß40 decreased correct choices, whereas increased errors (both number of arms revisited and total number of revisits) and latency of completing the maze test. The ßSBPs decreased Aß40-induced pathological changes, memory impairment and Aß40 expression in serum. The ßSBP15-22 distinctively decreased the total errors on day 14. The present results show that octapeptide ßSBPs corrected Aß40-induced memory impairment, and support investigation of ßSBPs as a promising treatment of diseases characterized by neurodegeneration and memory impairment such as Alzheimer's disease.
Subject(s)
Aging/metabolism , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Memory Disorders/drug therapy , Peptide Fragments/antagonists & inhibitors , Aging/pathology , Alzheimer Disease/blood , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/genetics , Animals , Disease Models, Animal , Male , Memory Disorders/blood , Memory Disorders/physiopathology , Peptide Fragments/blood , Peptide Fragments/genetics , Rats , Rats, Sprague-DawleyABSTRACT
In vivo microdialysis combined with high performance liquid chromatography (HPLC) with electrochemical detection, was used to study the effect of MK-801 (0.1 mg/kg i.p.) on extracellular concentrations of dopamine (DA) 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), norepinephrine (NE) and DOPAC/DA ratio in intact, 6-hydroxydopamine (6-OHDA)-lesioned, DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzyl-amine hydrochloride)-lesioned and reserpine-treated rats. The results revealed high basal DA (0.735+/-0.05 fmol/microl), DOPAC (195.93+/-20.18 fmol/microl) and NE (0.585+/-0.01 fmol/microl), low 5-HT (0.334+/-0.032 fmol/microl) and high DOPAC/DA ratio (265.11+/-20.73) in intact cACC. 6-OHDA alone (8 microg/2 microl) depleted DA (-66%), DOPAC (-65%), and NE (-62%). On the other hand, in desipramine (DMI)-pretreated rats, 6-OHDA induced a large depletion of DA (-94%), DOPAC (-97%) and reduced DOPAC/DA ratio (-73%), but increased NE to 142% of intact and 369% of 6-OHDA-lesioned rats. DSP4 (50 mg/kg) decreased NE (-97%), DOPAC (-75%) and DOPAC/DA ratio (-69%). Reserpine (5 mg/kg s.c.) significantly decreased DOPAC (-84%), DOPAC/DA ratio (-81%), 5-HT (-69%) and NE (-86%), but nonsignificantly increased DA. In the intact rats, MK-801 did not change DA, but increased DOPAC and DOPAC/DA ratio. In 6-OHDA-lesioned rats, MK-801 increased DA, whereas in 6-OHDA+DMI rats MK-801 additionally increased DOPAC and DOPAC/DA ratio. DSP4 and reserpine reduced the ability of MK-801 to increase DOPAC and DOPAC/DA ratio. MK-801 did not change NE concentration in dialysates collected from intact rats, but increased that from 6-OHDA+DMI-lesioned rats. In DSP4-lesioned and reserpine-treated rats, MK-801 increased NE but to a level lower than that observed in the intact rats. These results suggest that systemic administration of a low dose of MK-801, which induces profound locomotor stimulation without stereotypy, increases DOPAC and DOPAC/DA ratio in the cACC of intact rats, whereas it additionally increases the depleted DA and NE concentrations especially in 6-OHDA-lesioned rats pretreated with DMI.
Subject(s)
Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Neuroprotective Agents/pharmacology , Neurotransmitter Agents/metabolism , Nucleus Accumbens/drug effects , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Benzylamines/toxicity , Chromatography, High Pressure Liquid , Desipramine/pharmacology , Dopamine/metabolism , Male , Microdialysis , Motor Activity/drug effects , Norepinephrine/metabolism , Nucleus Accumbens/metabolism , Oxidopamine/toxicity , Rats , Rats, Wistar , Reserpine/toxicity , Serotonin/metabolismABSTRACT
In this study we investigated the effect of lesioning the noradrenergic systems on the behavioral effects of (5R, 10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrogen maleate--MK-801, in rats. The noradrenergic system was lesioned with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride--DSP4 (60 mg/kg IP). MK-801 increased the locomotor activity and rearing. DSP4 significantly further increased the hyperlocomotor activity, circling (especially to the left side), sniffing, rolling, and falling that were induced by MK-801. These results showed that destruction of the noradrenergic system increased MK-801-hyperlocomotor activity, ataxia and stereotypy.
