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Protective effect of valproic acid in streptozotocin-induced sporadic Alzheimer's disease mouse model: possible involvement of the cholinergic system.

Abstract Sporadic Alzheimer's disease (SAD) is a slowly progressive neurological disorder that is the most common form of dementia. Cholinergic system dysfunction and amyloid beta formation are the two main underlying pathological mechanisms for the disease development. In recent studies, insulin receptor desensitization and disturbances in the downstream effects of insulin receptor signaling were observed in the brains of Alzheimer's patients. Currently, intracereberoventricular (ICV) injection of streptozotocin (STZ) is found to induce behavioral, neurochemical, and structural alterations in animals resembling those found in SAD patients. Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), was recently shown to regulate the transcription of several genes in both in vivo and in vitro models of Alzheimer's disease. The aim of the current study is to investigate the potential effect of different doses of valproic acid, in an ICV-STZ-induced animal model of SAD. Streptozotocin-injected mice showed cognitive and spatial memory dysfunction in the Y-maze, object recognition test, and Morris water maze (MWM) neurobehavioral tests. The mice also exhibited a decrease in acetylcholine (ACh) and neprilysin (NEP) levels accompanied by an increase in acetylcholinesterase (AChE) activity. For the first time to our knowledge, our findings have shown that VPA is capable of restoring ACh levels in ICV-STZ-injected mice, as well as normalizing both NEP levels and AChE activity. Via this mechanism, an enhancement of cognitive functions is observed. Thus, VPA is suggested to be a promising therapeutic approach against SAD.
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Authors

Mayor MeshTerms
Keywords

Alzheimer’s disease

Cholinergic system

Intracerebroventricular

Streptozotocin

Valproic acid

Journal Title naunyn-schmiedeberg's archives of pharmacology
Publication Year Start




PMID- 28188358
OWN - NLM
STAT- Publisher
DA  - 20170211
LR  - 20170211
IS  - 1432-1912 (Electronic)
IS  - 0028-1298 (Linking)
DP  - 2017 Feb 10
TI  - Protective effect of valproic acid in streptozotocin-induced sporadic Alzheimer's
      disease mouse model: possible involvement of the cholinergic system.
LID - 10.1007/s00210-017-1357-4 [doi]
AB  - Sporadic Alzheimer's disease (SAD) is a slowly progressive neurological disorder 
      that is the most common form of dementia. Cholinergic system dysfunction and
      amyloid beta formation are the two main underlying pathological mechanisms for
      the disease development. In recent studies, insulin receptor desensitization and 
      disturbances in the downstream effects of insulin receptor signaling were
      observed in the brains of Alzheimer's patients. Currently,
      intracereberoventricular (ICV) injection of streptozotocin (STZ) is found to
      induce behavioral, neurochemical, and structural alterations in animals
      resembling those found in SAD patients. Valproic acid (VPA), a histone
      deacetylase inhibitor (HDACi), was recently shown to regulate the transcription
      of several genes in both in vivo and in vitro models of Alzheimer's disease. The 
      aim of the current study is to investigate the potential effect of different
      doses of valproic acid, in an ICV-STZ-induced animal model of SAD.
      Streptozotocin-injected mice showed cognitive and spatial memory dysfunction in
      the Y-maze, object recognition test, and Morris water maze (MWM) neurobehavioral 
      tests. The mice also exhibited a decrease in acetylcholine (ACh) and neprilysin
      (NEP) levels accompanied by an increase in acetylcholinesterase (AChE) activity. 
      For the first time to our knowledge, our findings have shown that VPA is capable 
      of restoring ACh levels in ICV-STZ-injected mice, as well as normalizing both NEP
      levels and AChE activity. Via this mechanism, an enhancement of cognitive
      functions is observed. Thus, VPA is suggested to be a promising therapeutic
      approach against SAD.
FAU - Sorial, Mirna Ezzat
AU  - Sorial ME
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology,
      German University in Cairo, Main Entrance of Al Tagamoa Al Khames, New Cairo
      City, 11835, Egypt.
FAU - El Sayed, Nesrine Salah El Dine
AU  - El Sayed NS
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology,
      German University in Cairo, Main Entrance of Al Tagamoa Al Khames, New Cairo
      City, 11835, Egypt. [email protected]
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University,
      Giza, 12613, Egypt. [email protected]
LA  - eng
PT  - Journal Article
DEP - 20170210
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Cholinergic system
OT  - Intracerebroventricular
OT  - Streptozotocin
OT  - Valproic acid
EDAT- 2017/02/12 06:00
MHDA- 2017/02/12 06:00
CRDT- 2017/02/12 06:00
PHST- 2016/11/01 [received]
PHST- 2017/02/01 [accepted]
AID - 10.1007/s00210-017-1357-4 [doi]
AID - 10.1007/s00210-017-1357-4 [pii]
PST - aheadofprint
SO  - Naunyn Schmiedebergs Arch Pharmacol. 2017 Feb 10. doi: 10.1007/s00210-017-1357-4.

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