Lamotrigine prevents MK801-induced alterations in early growth response factor-1 mRNA levels and immunoreactivity in the rat brain.
MK801 (dizocilpine) induces selective neurotoxic effects in the retrosplenial cortex, ranging from neuronal vacuolization to irreversible neurodegeneration depending on the dose administered. Although lamotrigine prevents MK801-induced neuronal vacuolization in the retrosplenial cortex 4 h after injection, it is not clear whether lamotrigine attenuates the subsequent neurodegeneration that occurs 3-4 days later. Because early growth response factor-1 (egr-1) plays a key role in neurodegeneration and its expression is induced in the retrosplenial cortex following MK801 treatment, it is possible that lamotrigine may attenuate MK801-induced neurodegeneration via inhibition of egr-1 expression in the retrosplenial cortex. To address this issue, we treated rats with lamotrigine (10 or 20 mg/kg) followed by MK801 (2 mg/kg) and measured changes in the levels of egr-1 mRNA and immunoreactivity in the retrosplenial cortex and other brain regions 3 h later. We also evaluated the effects of these treatments on neurodegeneration 4 days following treatment using Fluoro-Jade B staining. MK801 treatment increased egr-1 mRNA and immunoreactivity in the restrosplenial, cingulate, entorhinal and piriform cortices, but decreased levels in hippocampal subfields. These MK801-induced changes in egr-1 expression were significantly inhibited by lamotrigine pretreatment. In addition, MK801-induced neurodegeneration in the retrosplenial cortex was partially blocked by lamotrigine pretreatment in a dose dependent manner. These results demonstrate that lamotrigine pretreatment prevents the MK801-induced upregulation of egr-1 expression in a region-selective manner, and suggest that this effect may contribute, in part, to the attenuation of MK801-induced neurodegeneration in the retrosplenial cortex.
Park
Sang-Ha
SH
Department of Pharmacology, Korea University College of Medicine, Sungbuk-Gu, Seoul, Republic of Korea.
Seo
Young Ho
YH
Moon
Bo-Hyun
BH
Choi
Song-Hyen
SH
Kang
Seungwoo
S
Lee
Kuem-Ju
KJ
Choi
Sang-Hyun
SH
Lee
Min-Soo
MS
Chun
Boe-Gwun
BG
Shin
Kyung-Ho
KH
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D000077213:Lamotrigine; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D014227:Triazines; D016291:Dizocilpine Maleate; D000077213:Lamotrigine