The immunosuppressant FK506 elicits a neuronal heat shock response and protects against acrylamide neuropathy.
Acrylamide (AC) is a known industrial neurotoxic chemical that has been recently found in carbohydrate-rich foods cooked at high temperatures. Repeated AC administration produces a pronounced neuropathy characterized by flaccid paralysis and ataxia and represents a well-established animal model of progressive axonal loss. AC also elicits prominent morphologic alterations (e.g., eccentrically placed nuclei, infolding of the nuclear membrane, accumulations of dense bodies, and clusters of smooth endoplasmic reticulum (SER) associated with numerous microtubules) in cerebellar Purkinje cells that may contribute to the pronounced ataxia in these animals. Here, we examined the neuroprotective action of FK506 (tacrolimus) in male and female rats given daily intraperitoneal injections of AC (30 mg/kg) for 4 weeks. Daily subcutaneous injections of FK506 (2 mg/kg/day) dramatically reduced the behavioral signs of neuropathy (i.e., paralysis and ataxia), markedly protected against axonal loss (by 82% and 73% in the tibial nerves of male and female rats, respectively), and reduced the pathologic changes in Purkinje cells. In a separate study, subcutaneous injections of FK506 (2 or 10 mg/kg) for 2 weeks markedly increased heat shock protein-70 (Hsp-70) immunostaining in sensory neurons, motor neurons, Purkinje cells, and other regions of the brain (in particular, the amygdala) from nonintoxicated and AC-intoxicated rats compared to controls. In contrast, AC-intoxicated animals not given FK506 demonstrated reduced Hsp-70 staining. Thus, the ability of FK506 to increase Hsp-70 expression may underlie its neuroprotective action. We suggest that compounds capable of eliciting a heat shock response may be useful for the treatment of human neuropathies.
Gold
Bruce G
BG
Center for Research on Occupational and Environmental Toxicology and Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239-3098, USA. gold@ohsu.edu
Voda
Jan
J
Yu
Xiaolin
X
Gordon
Heidi
H
D020106:Acrylamide; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D018869:Heat-Shock Response / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D016559:Tacrolimus / Q000494:pharmacology*
D018840:HSP70 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D016760:Proto-Oncogene Proteins c-fos; D020106:Acrylamide; D016559:Tacrolimus