The neuroprotective effects of the recombinant interleukin-1 receptor antagonist rhIL-1ra after excitotoxic stimulation with kainic acid and its relationship to the amyloid precursor protein gene.
The cytokine interleukin-1 (IL-1) and its endogenous antagonist (IL-1ra) have important functions in the central nervous system. Recent experimental observations have suggested that recombinant IL-1RA (rhIL-1ra) has neuroprotective properties in ischaemia, excitotoxicity, and trauma. We wished to see what effect rhIL-1ra had on kainic acid-induced neuronal death and to investigate how this might relate to changes in expression of the amyloid precursor protein gene (APP) and glial fibrillary acid protein (GFAP) using in situ hybridization. Wistar rats were treated by intracerebroventricular administration with rhIL-1ra at doses of 10, 20 and 40 microg given 10 min before and 10 min after intraperitoneal kainic acid 10 mg/kg. Behaviour was measured and, after 10 days, the brains were removed for histology and in situ hybridization. There were no anticonvulsant effects on kainic acid-induced wet dog shakes or limbic motor seizures. There were no differences in the effects of rhIL-1ra at all doses tested on hippocampal temperature, blood pressure, blood gases, pH, and glucose in comparison to control. With rhIL-1ra 10 microg given twice, there was significant protection of neurons in the CA1 and CA3 field of the hippocampus and dorsal thalamus, but not in the primary olfactory cortex-amygdaloid region. Small, but insignificant, neuroprotective effects were observed in the same anatomical regions with a dose of 20 microg given twice, and no neuroprotective effects were observed with 40 microg. The enhanced neuronal survival in CA1, CA3 and the dorsal thalamus was associated with preservation of APP 695 mRNA (neuronal form) and lack of stimulation of APP 770 (glial form) and GFAP messages. Where there was no neuroprotection APP 695 mRNA was reduced and stimulation of both APP 770 and GFAP mRNAs was observed. In conclusion, rhIL-1ra has dose- and region-dependent effects on neuronal survival after kainic acid and prevents damage-induced changes in APP and GFAP mRNAs.
Panegyres
P K
PK
Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, UK.
Hughes
J
J
D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013268:Stimulation, Chemical; D014361:Trypsin Inhibitors / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D014361:Trypsin Inhibitors; D007608:Kainic Acid