Overcoming macrophage-mediated axonal dieback following CNS injury.
J Neurosci. 2009 Aug 12; 29(32): 9967-76Busch SA, Horn KP, Silver DJ, Silver JTrauma to the adult CNS initiates multiple processes including primary and secondary axotomy, inflammation, and glial scar formation that have devastating effects on neuronal regeneration. After spinal cord injury, the infiltration of phagocytic macrophages coincides with long-distance axonal retraction from the initial site of injury, a deleterious phenomenon known as axonal dieback. We have previously shown that activated macrophages directly induce long-distance retraction of dystrophic axons in an in vitro model of the glial scar. We hypothesized that treatments that are primarily thought to increase neuronal regeneration following spinal cord injury may in fact derive a portion of their beneficial effects from inhibition of macrophage-mediated axonal retraction. We analyzed the effects of protease inhibition, substrate modification, and neuronal preconditioning on macrophage-axon interactions using our established in vitro model. General inhibition of matrix metalloproteinases and specific inhibition of MMP-9 prevented macrophage-induced axonal retraction despite significant physical interactions between the two cell types, whereas inhibition of MMP-2 had no effect. Chondroitinase ABC-mediated digestion of the aggrecan substrate also prevented macrophage-induced axonal retraction in the presence of extensive macrophage-axon interactions. The use of a conditioning lesion to stimulate intrinsic neuronal growth potential in the absence of substrate modification likewise prevented macrophage-induced axonal retraction in vitro and in vivo following spinal cord injury. These data provide valuable insight into the cellular and molecular mechanisms underlying macrophage-mediated axonal retraction and demonstrate modifications that can alleviate the detrimental effects of this unfavorable phenomenon on the postlesion CNS.
The phenotype and potential origin of nestin cardiac myocyte-like cells following infarction.
In the infarcted human and rat heart, nestin((+)) cardiac myocyte-like cells were morphologically and structurally immature, exhibited a desmin-immunoreactive striated phenotype, expressed the beta1-adrenergic receptor and associated with an aberrant pattern of connexin-43 expression and/or organization.
Nestin((+)) cardiac myocyte-like cells were detected 24 hrs post ischemic injury and persisted in the infarcted rat heart for 9 months. In the normal rat heart, cardiac progenitor transcriptional factors Nkx2.5/GATA4 were detected in a subpopulation of nestin((+)) neural stem cells.
Following an ischemic insult, nestin((+))/Nkx2.5((+)) neural stem cells migrated to the peri-infarct/infarct region and appeared to be in a primordial state of differentiation to a nestin((+)) cardiac myocyte-like cell. The exposure of adult male rats to normobaric hypoxia (12% O2) for ten days failed to promote the appearance of nestin((+)) cardiac myocyte-like cells. Following osmotic pump delivery of isoproterenol to normal adult rats, nestin((+)) cardiac myocyte-like cells were detected, albeit the response was modest and secondary to tissue loss.
Thus, ischemia-induced appearance of nestin((+)) cardiac myocyte-like cells apparently represents an adaptive response to heal the infarcted heart. Nkx2.5/GATA4 expression in a subpopulation of resident neural stem cells provides the appropriate phenotype for their potential differentiation to a nestin((+)) cardiac myocyte-like cell.
"The phenotype and potential origin of nestin(+) cardiac myocyte-like cells following infarction".
J Appl Physiol. 2009 Aug 13; Beguin PC, El-Helou V, Assimakopoulos J, Clement R, Gosselin H, Brugada R, Villeneuve L, Rohlicek CV, Del Duca D, Lapointe N, Rouleau JL, Calderone A (Hubmed.org)
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Protein kinase Cdelta activation induces close homolog of adhesion molecule L1 (CHL1) expression in cultured astrocytes.
Here, we investigate the molecular mechanisms underlying upregulation of CHL1 expression by analyzing the signal transduction pathways in vitro. We show that astrogliosis stimulated by bacterial lipopolysaccharide (LPS) upregulates CHL1 expression in primary cultures of mouse cerebral astrocytes, coinciding with elevated protein synthesis and translocation of protein kinase delta (PKCdelta) from cytosol to the membrane fraction.
Blocking PKCdelta activity pharmacologically and genetically attenuates LPS-induced elevation of CHL1 protein expression through a phosphatidylinositol 3-kinase (PI3K) dependent pathway. LPS induces extracellular signal-regulated kinases (ERK1/2) phosphorylation through PKCdelta and blockade of ERK1/2 activation abolishes upregulation of CHL1 expression.
LPS-triggered upregulation of CHL1 expression mediated through translocation of nuclear factor kappaB (NF-kappaB) to the nucleus is blocked by a specific NF-kappaB inhibitor and by inhibition of PI3K, PKCdelta, and ERK1/2 activities, implicating NF-kappaB as a downstream target for upregulation of CHL1 expression. Furthermore, the LPS-mediated upregulation of CHL1 expression by reactive astrocytes is inhibitory for hippocampal neurite outgrowth in cocultures.
Although the LPS-triggered NO-guanylate cyclase-cGMP pathway upregulates glial fibrillary acid protein expression in cultured astrocytes, we did not observe this pathway to mediate LPS-induced upregulation of CHL1 expression.
Our results indicate that elevated CHL1 expression by reactive astrocytes requires activation of PI3K/PKCdelta-dependent pathways and suggest that reduction of PI3K/PKCdelta activity represents a therapeutic target to downregulate CHL1 expression and thus benefit axonal regeneration after SCI. (c) 2009 Wiley-Liss, Inc.
"Phosphatidylinositol 3-kinase/protein kinase Cdelta activation induces close homolog of adhesion molecule L1 (CHL1) expression in cultured astrocytes"
Glia. 2009 Aug 11; Wu J, Wrathall JR, Schachner MUp
Severe cutaneous adverse reactions
High-resolution HLA genotyping was performed for 65 patients of European ancestry treated with lamotrigine (22 cases with lamotrigine-induced SCARs and 43 controls on lamotrigine without SCAR-related symptoms). Association of HLA genetic variants with SCARs in these patients were evaluated by contrasting allele frequencies between the cases and the controls for each of 112 HLA four-digit alleles.
RESULTS:
Five alleles were observed with higher frequencies in the cases compared with the treated controls with exact P values less than 0.05.
In contrast to the study of carbamazepine-induced Stevens-Johnson syndrome in Han Chinese patients, none of the cases carried B*1502. Accounting for the large number of hypothesis tests conducted, none of the associations identified were statistically significant.
CONCLUSION:
No single major HLA-related genetic risk factor was identified for lamotrigine-induced SCARs in patients of European origin. Only suggestive evidence was obtained for B*5801, A*6801, Cw*0718, DQB1*0609, and DRB1*1301.
Confirmation of these results in a larger, independent sample is needed to determine whether any of the HLA alleles identified are truly associated with the development of lamotrigine-induced SCARs.
"High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients."
Pharmacogenet Genomics. 2009 Aug 6; Kazeem GR, Cox C, Aponte J, Messenheimer J, Brazell C, Nelsen AC, Nelson MR, Foot E
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