Specificity and divergence in the neurobiologic effects of different metallothioneins after brain injury.
Brain injury and neuroinflammation are pathophysiologic contributors to acute and chronic neurologic disorders, which are progressive diseases not fully understood. Mammalian metallothioneins I and II (MT-I&II) have significant neuroprotective functions, but the precise mechanisms underlying these effects are still unknown. To gain insight in this regard, we have evaluated whether a distant, most likely single-domain MT (Drosophila MTN) functions similarly to mammalian MT-I&II (recombinant mouse MT-I and human MT-IIa and native rabbit MT-II) after cryogenic injury to the cortex in Mt1&2 KO mice. All the recombinant proteins showed similar neuroprotective properties to native MT-II, significantly reducing brain inflammation (macrophages, T cells, and pro-inflammatory cytokines), oxidative stress, neurodegeneration, and apoptosis. These results in principle do not support specific protein-protein interactions as the mechanism underlying the neuroprotective effects of these proteins because a non-homologous and structurally unrelated MT such as Drosophila MTN functions similarly to mammalian MTs. We have also evaluated for the first time the neurobiologic effects of exogenous MT-III, a major CNS MT isoform. Human rMT-III, in contrast to human nMT-IIa, did not affect inflammation, oxidative stress, and apoptosis, and showed opposite effects on several growth factors, neurotrophins, and markers of synaptic growth and plasticity. Our data thus highlight specific and divergent roles of exogenous MT-III vs. the MT-I&II isoforms that are consistent with those attributed to the endogenous proteins, and confirm the suitability of recombinant synthesis for future therapeutic use that may become relevant to clinical neurology.
Penkowa
Milena
M
Section of Neuroprotection, Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Denmark.
Tio
Laura
L
Giralt
Mercedes
M
Quintana
Albert
A
Molinero
Amalia
A
Atrian
Silvia
S
Vasák
Milan
M
Hidalgo
Juan
J
D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D002452:Cell Count / Q000379:methods; D004347:Drug Interactions; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000145:classification / Q000172:deficiency / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D009446:Neurobiology / Q000379:methods*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism; D012680:Sensitivity and Specificity
D015703:Antigens, CD; D005904:Glial Fibrillary Acidic Protein; D011994:Recombinant Proteins; D008668:Metallothionein