AP-1 inhibitory peptides attenuate in vitro cortical neuronal cell death induced by kainic acid.
This study has assessed the neuroprotective efficacy of five AP-1 inhibitory peptides in an in vitro excitotoxicity model. The five AP-1 inhibitory peptides and controls of the JNK inhibitor peptide (JNKI-1D-TAT) and TAT cell-penetrating-peptide were administered to primary cortical neuronal cultures prior to kainic acid exposure. All five AP-1 inhibitory peptides and JNKI-1D-TAT provided significant neuroprotection from kainic acid induced neuronal cell death. Kainic acid exposure induced caspase and calpain activation in neuronal cultures, with caspase-induced cleavage of α-fodrin reduced by administration of the AP-1 inhibitory peptides. Sequence analysis of the AP-1 inhibitory peptides did not reveal the presence of any secondary structures; however two peptides shared 66% amino-acid sequence homology. As a result, truncated sequences were designed and synthesised to identify the active region of the peptides. All truncated peptides were significantly neuroprotective following kainic acid and glutamate exposure. We have shown for the first time the neuroprotective efficacy of full-length and truncated AP-1 inhibitory peptides in kainic acid and glutamate neuronal excitotoxicity models. The identification of therapeutic targets, such as the AP-1 complex, is an important step for the development of pharmaceuticals to reduce neuronal loss in disorders with a prevalence of excitotoxic cell death such as epilepsy, cerebral ischaemia, and traumatic brain injury.
Meade
Amanda J
AJ
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, QEII Medical Centre, Nedlands, WA, Australia.
Meloni
Bruno P
BP
Mastaglia
Frank L
FL
Watt
Paul M
PM
Knuckey
Neville W
NW
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D015696:Gene Products, tat / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D013049:Spectrin
D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D015696:Gene Products, tat; D018698:Glutamic Acid; D007608:Kainic Acid; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D010455:Peptides; D018808:Transcription Factor AP-1; D013049:Spectrin