Effect of Sodium Valproate Administration on Brain Neprilysin Expression and Memory in Rats

Abstract

Alzheimer's disease (AD) is accompanied by memory loss due to neuronal cell death caused by toxic amyloid β-peptide (Aβ) aggregates. In the healthy brain, a group of amyloid-degrading enzymes including neprilysin (NEP) maintain Aβ levels at physiologically low concentrations but, with age and under some pathological conditions, expression and activity of these enzymes decline predisposing to late-onset AD. Hence, up-regulation of NEP might be a viable strategy for prevention of Aβ accumulation and development of the disease. As we have recently shown, inhibitors of histone deacetylases, in particular, valproic acid (VA), were capable of up-regulating NEP expression and activity in human neuroblastoma SH-SY5Y cell lines characterised by very low levels of NEP. In the present study, analysing the effect of i.p. injections of VA to rats, we have observed up-regulation of expression and activity of NEP in rat brain structures, in particular, in the hippocampus. This effect was brain region- and age-specific. Administration of VA has also restored NEP activity and memory deficit in adult rats caused by prenatal hypoxia. This suggests that VA and more specific HDAC inhibitors can be considered as potential pharmaceutical agents for up-regulation of NEP activity and improvement of cognitive functions of ageing brain.

Human neuronal cells: epigenetic aspects

“…Treatment with HDAC inhibitors (Table 2 ), valproic acid (VPA) and trichostatin A (TSA), significantly increased NEP expression and enzymatic activity in SH-SY5Y cells but not in the NB7 cell line, suggesting A β clearance can be reinstated via chromatin remodeling. Chromatin immunoprecipitation analysis using anti-HDAC1 and anti-AICD antibodies revealed an increase in AICD binding to NEP promoter regions, which paralleled a decrease in HDAC1 binding within the SH-SY5Y cells after TSA treatment (60) , which was also consistent with a subsequent in vivo study (63) . These results indicate that HDAC1 silences NEP expression at promoter regions, and the downregulation exposes the NEP promoter and assists in AICD binding.…”

The activity of blood serum cholinesterases and neprilysin as potential biomarkers of mild-cognitive impairment and Alzheimer’s disease

“…Этиология ее возникновения и развития имеет много-факторную природу. Одним из факторов, способству-ющих возникновению спорадической формы БА, явля-ется нарушение катаболизма Аβ и его выведение из нервной ткани [14], часто обусловленное снижением активности амилоид-деградирующих ферментов, в частности неприлизина (EC3.4.24.11, нейтральная эн-допептидаза, НЕП) [7,15,16], а также нарушением ха-рактера связывания Аβ с белками-переносчиками, как, например, в случае экспрессии аллели АроЕ ε4 [17].…”

“…Данные литературы также свидетельствуют о том, что со-держание мРНК НЕП и активность его гомолога НЕП2 снижается в средневисочной и среднелобной извилинах, хвостатом ядре и мозжечке головного мозга пациентов с синдромом мягкого когнитивного снижения амнестиче-ского типа (а-MКC) и БА [22]. Дефицит активности НЕП в коре и гиппокампе также наблюдается у животных с на-рушенными когнитивными функциями [16,[23][24][25][26][27].…”

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

“…Considering the ability of fingolimod to inhibit HDAC [20] and the role of HDAC inhibitors including valproate and lacosamide in enhancing learning and memory processes and the epigenetic modulation of absence seizure development in this model [27,[75][76][77][78][79], we studied fingolimod ELTT effects on acetylation of Lysine 8 of histone H4 (both 6 and 10 months of age) and found a significant increase temporally linked to the preserved cognitive functions.…”