PMID- 34481907
OWN - NLM
STAT- MEDLINE
DCOM- 20220223
LR  - 20220223
IS  - 1872-9754 (Electronic)
IS  - 0197-0186 (Linking)
VI  - 150
DP  - 2021 Nov
TI  - Inhibition of mitochondrial pyruvate carrier 1 by lapatinib ditosylate mitigates 
      Alzheimer's-like disease in D-galactose/ovariectomized rats.
PG  - 105178
LID - S0197-0186(21)00224-2 [pii]
LID - 10.1016/j.neuint.2021.105178 [doi]
AB  - Mitochondrial, autophagic impairment, excitotoxicity, and also neuroinflammation 
      are implicated in Alzheimer's disease (AD) pathophysiology. We postulated that 
      inhibiting the mitochondrial pyruvate carrier-1 (MPC-1), which inhibits the 
      activation of the mammalian target of rapamycin (mTOR), may ameliorate the 
      neurodegeneration of hippocampal neurons in the rat AD model. To assess this, we 
      used lapatinib ditosylate (LAP), an anti-cancer drug that inhibits MPC-1 through 
      suppression of estrogen-related receptor-alpha (ERR-alpha), in 
      D-galactose/ovariectomized rats. AD characteristics were developed in 
      ovariectomized (OVX) rats following an 8-week injection of D-galactose (D-gal) 
      (150 mg/kg, i.p.). The human epidermal growth factor receptor-2 (HER-2) 
      inhibitor, LAP (100 mg/kg, p.o.) was daily administered for 3 weeks. LAP 
      protected against D-gal/OVX-induced changes in cortical and hippocampal neurons 
      along with improvement in learning and memory, as affirmed using Morris water 
      maze (MWM) and novel object recognition (NOR) tests. Furthermore, LAP suppressed 
      the hippocampal expression of Abeta1-42, p-tau, HER-2, p-mTOR, GluR-II, TNF-alpha, 
      P38-MAPK, NOX-1, ERR-alpha, and MPC-1. Also, LAP treatment leads to activation of the 
      pro-survival PI3K/Akt pathway. As an epilogue, targeting MPC-1 in the 
      D-gal-induced AD in OVX rats resulted in the enhancement of autophagy, and 
      suppression of neuroinflammation and excitotoxicity. Our work proves that 
      alterations in metabolic signaling as a result of inhibiting MPC-1 were 
      anti-inflammatory and neuroprotective in the AD model, revealing that HER-2, 
      MPC-1, and ERR-alpha may be promising therapeutic targets for AD.
CI  - Copyright (c) 2021 Elsevier Ltd. All rights reserved.
FAU - Mansour, Heba M
AU  - Mansour HM
AD  - Department of Pharmacology, Egyptian Drug Authority, EDA, formerly NODCAR, Giza, 
      Egypt. Electronic address: heba.mo.mansour@std.pharma.cu.edu.eg.
FAU - Fawzy, Hala M
AU  - Fawzy HM
AD  - Department of Pharmacology, Egyptian Drug Authority, EDA, formerly NODCAR, Giza, 
      Egypt.
FAU - El-Khatib, Aiman S
AU  - El-Khatib AS
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 
      Cairo, Egypt.
FAU - Khattab, Mahmoud M
AU  - Khattab MM
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 
      Cairo, Egypt.
LA  - eng
PT  - Journal Article
DEP - 20210903
PL  - England
TA  - Neurochem Int
JT  - Neurochemistry international
JID - 8006959
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Monocarboxylic Acid Transporters)
RN  - 0 (Mpc1 protein, rat)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Solute Carrier Proteins)
RN  - 0VUA21238F (Lapatinib)
RN  - X2RN3Q8DNE (Galactose)
SB  - IM
MH  - Alzheimer Disease/chemically induced/etiology/*metabolism/*prevention & control
MH  - Animals
MH  - Female
MH  - Galactose/*toxicity
MH  - Lapatinib/*pharmacology/therapeutic use
MH  - Maze Learning/drug effects/physiology
MH  - Mitochondrial Proteins/*antagonists & inhibitors/metabolism
MH  - Monocarboxylic Acid Transporters/*antagonists & inhibitors/metabolism
MH  - Ovariectomy/*adverse effects/trends
MH  - Protein Kinase Inhibitors/pharmacology/therapeutic use
MH  - Rats
MH  - Rats, Wistar
MH  - Solute Carrier Proteins/*antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Estrogen-related receptor-alpha
OT  - Human epidermal growth factor receptor-2
OT  - Lapatinib ditosylate
OT  - Mitochondrial pyruvate carrier-1
EDAT- 2021/09/06 06:00
MHDA- 2022/02/24 06:00
CRDT- 2021/09/05 20:37
PHST- 2021/08/16 00:00 [received]
PHST- 2021/08/19 00:00 [revised]
PHST- 2021/09/01 00:00 [accepted]
PHST- 2021/09/06 06:00 [pubmed]
PHST- 2022/02/24 06:00 [medline]
PHST- 2021/09/05 20:37 [entrez]
AID - S0197-0186(21)00224-2 [pii]
AID - 10.1016/j.neuint.2021.105178 [doi]
PST - ppublish
SO  - Neurochem Int. 2021 Nov;150:105178. doi: 10.1016/j.neuint.2021.105178. Epub 2021 
      Sep 3.