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Correspondence  |   November 2009
Role of p75 Neurotrophin Receptor in Isoflurane-mediated Neuronal Changes
Author Affiliations & Notes
  • Moeen K. Panni, M.D., Ph.D.
    *
  • *University of Florida College of Medicine, Jacksonville, Florida.
Article Information
Correspondence
Correspondence   |   November 2009
Role of p75 Neurotrophin Receptor in Isoflurane-mediated Neuronal Changes
Anesthesiology 11 2009, Vol.111, 1162-1163. doi:10.1097/ALN.0b013e3181bbc177
Anesthesiology 11 2009, Vol.111, 1162-1163. doi:10.1097/ALN.0b013e3181bbc177
To the Editor:—
We read with interest the article by Head et al.  , investigating the role of p75 neurotrophin receptor (p75NTR) in isoflurane-mediated neuronal changes.1 The central premise presented is that isoflurane neurotoxicity results mainly from the prevention of activity-dependent release of tissue plasminogen activator (tPA). tPA converts plasminogen to plasmin, which then cleaves probrain-derived neurotrophic factor to mature brain-derived neurotrophic factor.2 In the absence of tPA, excess probrain-derived neurotrophic factor levels are thought to activate a p75NTR-mediated synaptic reduction and increase cleaved caspase 3 levels. The increased cleaved caspase 3 is assumed to indicate increased apoptosis; however, no other evidence is presented of this, such as terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling staining at a 24-/48-h time point.3 
There is no investigation as to why this isoflurane-mediated toxicity is only seen in early neuronal cultures and early postnatal ages. We would like to suggest that this may be because of altered p75NTRexpression levels. There is an inverse relationship to p75NTRlevels in the hippocampus with age.4,5 The absence of isoflurane effects at postnatal Day 21 may in part be a result of lower or redistributed p75NTRlevels. The apoptotic pathway via  p75NTRcould also require additional coreceptors/cofactors that are themselves developmentally regulated.
The cell culture experiments are confounded by the fact that mixed neonatal cortex and hippocampal cultures are used. This would mean that there is inherent variation in neurite morphologies. No plating density is given, but we assume that 5 days in vitro  (DIV) cultures have low numbers of cell-cell contacts, whereas by DIV-14 or 21, a neurite network has been established.
In addition to changing p75NTRlevels with neuronal development and culture times, we suggest that isoflurane treatment may also alter the level of p75NTR. In figure 2D, isoflurane treatment of DIV-5 cultures in the presence of tPA seems to increase levels of phosphorylated Akt, as compared with control tPA treated DIV-5 cultures. As well as Akt phosphorylation via  the tropomyosin receptor kinase signaling pathway, p75NTRhas been shown to increase phosphorylated Akt in some systems using the neurotrophin NGF.6 In figure 4C, when DIV-5 cultures were treated with control small interfering ribonucleic acid, the isoflurane treated cultures had a higher level of p75NTRthan control cultures. p75NTRstaining of cultures or western blot analysis of p75NTRlevels would allow this hypothesis to be further investigated.
In addition to the regulation of tPA secretion, p75NTRlevels are also an important determinant of isoflurane-mediated neuronal changes. In summary, there may be a two-part mechanism to the isoflurane-mediated neuronal response, an increase in p75NTRlevels, and a decrease in tPA release, a threshold of which is required to obtain the isoflurane-mediated neuronal changes.
*University of Florida College of Medicine, Jacksonville, Florida.
References
Head BP, Patel HH, Niesman IR, Drummond JC, Roth DM, Patel PM: Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology 2009; 110:813–25Head, BP Patel, HH Niesman, IR Drummond, JC Roth, DM Patel, PM
Gray K, Ellis V: Activation of pro-BDNF by the pericellular serine protease plasmin. FEBS Lett 2008; 582:907–10Gray, K Ellis, V
Wise-Faberowski L, Pearlstein RD, Warner DS: NMDA-induced apoptosis in mixed neuronal/glial cortical cell cultures: The effects of isoflurane and dizocilpine. J Neurosurg Anesthesiol 2006; 18:240–6Wise-Faberowski, L Pearlstein, RD Warner, DS
Yang J, Siao CJ, Nagappan G, Marinic T, Jing D, McGrath K, Chen ZY, Mark W, Tessarollo L, Lee FS, Lu B, Hempstead BL: Neuronal release of proBDNF. Nat Neurosci 2009; 12:113–55Yang, J Siao, CJ Nagappan, G Marinic, T Jing, D McGrath, K Chen, ZY Mark, W Tessarollo, L Lee, FS Lu, B Hempstead, BL
Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B: Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 2005; 8:1069–77Woo, NH Teng, HK Siao, CJ Chiaruttini, C Pang, PT Milner, TA Hempstead, BL Lu, B
Roux PP, Bhakar AL, Kennedy TE, Barker PA: The p75 neurotrophin receptor activates Akt (protein kinase B) through a phosphatidylinositol 3-kinase-dependent pathway. J Biol Chem 2001; 276:23097–104Roux, PP Bhakar, AL Kennedy, TE Barker, PA