Fingolimod (FTY720) attenuates social deficits, learning and memory impairments, neuronal loss and neuroinflammation in the rat model of autism.
OBJECTIVE
To investigate the effect of FTY720 on the valproic acid (VPA) rat model of autism.


METHODS
As an animal model of autism, we used intraperitoneal injection of VPA on embryonic day 12.5 in Wistar rats. The pups were given FTY720 orally at doses of 0.25, 0.5 and 1mg/kg daily from postnatal day 15 to 35. Social behavior, spatial learning and memory were assessed at the end of FTY720 treatment. The histological change, oxidative stress, neuroinflammatory responses, and apoptosis-related proteins in the hippocampus were evaluated.


RESULTS
FTY720 (1mg/kg) administration to VPA-exposed rats (1) improved social behavior, spatial learning and memory impairment; (2) resulted in a reduction in neuronal loss and apoptosis of pyramidal cells in hippocampal CA1 regions; (3) inhibited activation of microglial cells, in turn lowering the level of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-6 in the hippocampus; (4) changed Malondialdehyde (MDA) levels, Glutathione (GSH) levels, superoxide dismutase (SOD) activity and Glutathione Peroxidase (GSH-Px) activity in the hippocampus; (6) inhibited the elevated Bax and caspase-3 protein levels and enhanced the relative expression level of Bcl-2 in the hippocampus; and (7) increased phospho-Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), phospho-cAMP-response element binding protein (p-CREB) and Brain Derived Neurotrophic Factor (BDNF) protein expression in the hippocampus.


CONCLUSIONS
FTY720 rescues social deficit, spatial learning and memory impairment in VPA-exposed rats. FTY720 exerts both a direct protection for neurons and an indirect modulation of inflammation-mediated neuron loss as a possible mechanism of neuroprotection.
Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, China.
Hongmei
H
Wu
Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, China.
Xuelai
X
Wang
Department of Nursing, Harbin Medical University in Daqing, Daqing, Heilongjiang 163319, China.
Jingquan
J
Gao
Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, China.
Shuang
S
Liang
Department of pediatrics, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, China.
Yanqiu
Y
Hao
Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, China.
Caihong
C
Sun
Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, China.
Wei
W
Xia
Department of Pharmacology, Harbin Medical University in Daqing, Daqing, Heilongjiang 163319, China. Electronic address: 437343482@qq.com.
Yonggang
Y
Cao
Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, China. Electronic address: wulijiehyd@126.com.
Lijie
L
Wu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001321:Autistic Disorder / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000009:adverse effects* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007858:Learning / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012919:Social Behavior
D051017:Apoptosis Regulatory Proteins; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D008315:Malondialdehyde; D010088:Oxidoreductases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000068876:Fingolimod Hydrochloride
Autism spectrum disorder; Fingolimod (FTY720); Hippocampal cell; Neuroinflammatory; Oxidative stress; VPA