Neuroprotective properties of the natural vitamin E alpha-tocotrienol.
OBJECTIVE
The current work is based on our previous finding that in neuronal cells, nmol/L concentrations of alpha-tocotrienol (TCT), but not alpha-tocopherol (TCP), blocked glutamate-induced death by suppressing early activation of c-Src kinase and 12-lipoxygenase.


METHODS
The single neuron microinjection technique was used to compare the neuroprotective effects of TCT with that of the more widely known TCP. Stroke-dependent brain tissue damage was studied in 12-Lox-deficient mice and spontaneously hypertensive rats orally supplemented with TCT.


RESULTS
Subattomole quantity of TCT, but not TCP, protected neurons from glutamate challenge. Pharmacological as well as genetic approaches revealed that 12-Lox is rapidly tyrosine phosphorylated in the glutamate-challenged neuron and that this phosphorylation is catalyzed by c-Src. 12-Lox-deficient mice were more resistant to stroke-induced brain injury than their wild-type controls. Oral supplementation of TCT to spontaneously hypertensive rats led to increased TCT levels in the brain. TCT-supplemented rats showed more protection against stroke-induced injury compared with matched controls. Such protection was associated with lower c-Src activation and 12-Lox phosphorylation at the stroke site.


CONCLUSIONS
The natural vitamin E, TCT, acts on key molecular checkpoints to protect against glutamate- and stroke-induced neurodegeneration.
Khanna
Savita
S
Department of Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA.
Roy
Sashwati
S
Slivka
Andrew
A
Craft
Tara K S
TK
Chaki
Soma
S
Rink
Cameron
C
Notestine
Margaret A
MA
DeVries
A Courtney
AC
Parinandi
Narasimham L
NL
Sen
Chandan K
CK
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001921:Brain / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology; D005452:Fluoresceins; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009930:Organic Chemicals / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D024508:Tocotrienols; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D000975:Antioxidants; D005452:Fluoresceins; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D024508:Tocotrienols; C435731:fluoro jade; D014810:Vitamin E; D018698:Glutamic Acid; D014443:Tyrosine; C082032:tocotrienol, alpha; D001092:Arachidonate 12-Lipoxygenase; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases