Sodium selenate retards epileptogenesis in acquired epilepsy models reversing changes in protein phosphatase 2A and hyperphosphorylated tau.
There are no treatments in clinical practice known to mitigate the neurobiological processes that convert a healthy brain into an epileptic one, a phenomenon known as epileptogenesis. Downregulation of protein phosphatase 2A, a protein that causes the hyperphosphorylation of tau, is implicated in neurodegenerative diseases commonly associated with epilepsy, such as Alzheimer's disease and traumatic brain injury. Here we used the protein phosphatase 2A activator sodium selenate to investigate the role of protein phosphatase 2A in three different rat models of epileptogenesis: amygdala kindling, post-kainic acid status epilepticus, and post-traumatic epilepsy. Protein phosphatase 2A activity was decreased, and tau phosphorylation increased, in epileptogenic brain regions in all three models. Continuous sodium selenate treatment mitigated epileptogenesis and prevented the biochemical abnormalities, effects which persisted after drug withdrawal. Our studies indicate that limbic epileptogenesis is associated with downregulation of protein phosphatase 2A and the hyperphosphorylation of tau, and that targeting this mechanism with sodium selenate is a potential anti-epileptogenic therapy.
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Shi-Jie
SJ
Liu
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Ping
P
Zheng
2 The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia 3 Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia.
David K
DK
Wright
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Gabi
G
Dezsi
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Emma
E
Braine
4 Department of Surgery, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Thanh
T
Nguyen
4 Department of Surgery, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Niall M
NM
Corcoran
2 The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia 5 Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, VIC, Australia.
Leigh A
LA
Johnston
4 Department of Surgery, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Christopher M
CM
Hovens
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Jamie N
JN
Mayo
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
Matthew
M
Hudson
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia sshultz@unimelb.edu.au ncjones@unimelb.edu.au obrientj@unimelb.edu.au.
Sandy R
SR
Shultz
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia sshultz@unimelb.edu.au ncjones@unimelb.edu.au obrientj@unimelb.edu.au.
Nigel C
NC
Jones
1 Department of Medicine, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia 6 Department of Neurology, Melbourne Brain Centre, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia sshultz@unimelb.edu.au ncjones@unimelb.edu.au obrientj@unimelb.edu.au.
Terence J
TJ
O'Brien
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000070642:Brain Injuries, Traumatic / Q000150:complications; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D007696:Kindling, Neurologic; D008279:Magnetic Resonance Imaging; D008297:Male; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D064586:Selenic Acid / Q000494:pharmacology*; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*
D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D016875:tau Proteins; C582184:Ppp2r2a protein, rat; D054648:Protein Phosphatase 2; D064586:Selenic Acid; D007608:Kainic Acid
MRI; PR55; animal model; epilepsy; traumatic brain injury