Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats.
Heat shock proteins (hsps) are induced in a variety of cells following periods of stress, where they promote cell survival. In this study, we examined the effect of upregulating hsp expression by treatment with BRX-220, a co-inducer of hsps, on the survival of injured motoneurones. Following sciatic nerve crush at birth, rat pups were treated daily with BRX-220. The expression of hsp70 and hsp90, motoneurone survival, and muscle function was examined at various intervals later and the number of functional motor units was assessed by in vivo isometric tension recordings. Fourteen days after injury, significantly more motoneurones survived in the BRX-220-treated group (39 +/- 2.8%) compared to the saline-treated group (21 +/- 1.7%). Moreover, in the BRX-220-treated group no further loss of motoneurones occurred, so that at 10 weeks 42 +/- 2.1% of motoneurones survived compared to 15 +/- 0.6% in the untreated group. There were also more functional motor units in the hindlimb muscles of BRX-220-treated animals. In addition, treatment with BRX-220 resulted in a significant increase in the expression of hsp70 and hsp90 in glia and neurones. Thus, treatment with BRX-220, a co-inducer of hsps, protects motoneurones from axotomy-induced cell death.
Kalmar
B
B
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, United Kingdom.
Burnstock
G
G
Vrbová
G
G
Urbanics
R
R
Csermely
P
P
Greensmith
L
L
D000818:Animals; D000831:Animals, Newborn; D019771:Axotomy; D015153:Blotting, Western; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006898:Hydroxylamines / Q000494:pharmacology*; D007150:Immunohistochemistry; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009409:Nerve Crush; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006898:Hydroxylamines; D018696:Neuroprotective Agents; C486387:arimoclomol