Can we switch microglia's phenotype to foster neuroprotection? Focus on multiple sclerosis

Microglia cells, the resident innate immune cells in the brain, are highly active, extending and retracting highly motile processes through which they continuously survey their microenvironment for ‘danger signals’ and interact dynamically with surrounding cells. Upon sensing changes in their central nervous system microenvironment, microglia become activated, undergoing morphological and functional changes. Microglia activation is not an ‘all‐or‐none’ process, but rather a continuum depending on encountered stimuli, which is expressed through a spectrum of molecular and functional phenotypes ranging from so‐called ‘classically activated’, with a highly pro‐inflammatory profile, to ‘alternatively activated’ associated with a beneficial, less inflammatory, neuroprotective profile. Microglia activation has been demonstrated in most neurological diseases of diverse aetiology and has been implicated as a contributor to neurodegeneration. The possibility to promote microglia’s neuroprotective phenotype has therefore become a therapeutic goal. We have focused our discussion on the role of microglia in multiple sclerosis, a prototype of inflammatory, demyelinating, neurodegenerative disease, and on the effect of currently approved or on‐trial anti‐inflammatory therapeutic strategies that might mediate neuroprotection at least in part through their effect on microglia by modifying their behaviour via a switch of their functional phenotype from a detrimental to a protective one. In addition to pharmaceutical approaches, such as treatment with glatiramer acetate, interferon‐β, fingolimod or dimethyl fumarate, we address the alternative therapeutic approach of treatment with mesenchymal stem cells and their potential role in neuroprotection through their ‘calming’ effect on microglia.     

Scanning electron microscopy of panitumumab-induced eyelash and hair alterations – Pili canaliculi

Panitumumab is a monoclonal antibody against the epidermal growth factor receptor used in metastatic colorectal cancer; in addition to tumor cells, it acts on epidermal keratinocytes and on the outer root sheath and presents skin toxicity in up to 90% of cases. A scanning electron microscope was used to examine the eyelashes and hairs of a 65-year-old patient with eyelash trichomegaly, curly hair, and paronychia undergoing treatment with panitumumab. Grooving in the hair shafts were identified, which were more evident in the eyelashes. Similar to oral epidermal growth factor inhibitors (erlotinib and gefitinib), panitumumab can cause acquired pili canaliculi.     

Teaching advanced operation of an iPod-based speech-generating device to two students with autism spectrum disorders

We evaluated a program for teaching two adolescents with autism spectrum disorders (ASD) to perform more advanced operations on an iPod-based speech-generating device (SGD). The effects of the teaching program were evaluated in a multiprobe multiple baseline across participants design that included two intervention phases. The first intervention focused on teaching the students to navigate between two screen pages and complete a multi-step response sequence to request preferred stimuli. The second intervention aimed to teach the students to turn on and unlock the device prior to navigating to the correct screen pages. Teaching procedures included response prompting, prompt fading, and differential reinforcement. Results showed that both interventions were effective in teaching the respective operations. Learning advanced operation of the iPod-based SGD could be seen as one way to promote greater independence in using such devices for multi-step communication.     

Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot

Two out of 47 patients with sporadic tetralogy of Fallot (TOF), the most common cyanotic conotruncal heart defect (CTD), showed heterozygous missense mutations of the ZFPM2/FOG2 gene. Knockout mice carrying mutations in the ZFPM2/FOG2 gene have similarly been found to exhibit TOF. While both mutant ZFPM2/FOG2 proteins, E30G (c.88A>G) and S657G (c.1968A>G), retain the ability to bind the partner protein GATA4 and repress GATA4 mediated gene activation, the S657G, but not the E30G, mutation is subtly impaired in this function. ZFPM2/FOG2 gene mutations may contribute to some sporadic cases of TOF.     

Cannabinoid CB(2) receptors modulate ERK-1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide

BACKGROUND AND PURPOSE

Cannabinoid (CB) receptor agonists have potential utility as anti-inflammatory drugs in chronic immune inflammatory diseases. In the present study, we characterized the signal transduction pathways affected by CB₂ receptors in quiescent and lipopolysaccharide (LPS)-stimulated murine microglia.

EXPERIMENTAL APPROACH

We examined the effects of the synthetic CB₂ receptor ligand, JWH-015, on phosphorylation of MAPKs and NO production.

KEY RESULTS

Stimulation of CB₂ receptors by JWH-015 activated JNK-1/2 and ERK-1/2 in quiescent murine microglial cells. Furthermore, CB₂ receptor activation increased p-ERK-1/2 at 15 min in LPS-stimulated microglia. Surprisingly, this was reduced after 30 min in the presence of both LPS and JWH-015. The NOS inhibitor l-NAME blocked the ability of JWH-015 to down-regulate the LPS-induced p-ERK increase, indicating that activation of CB₂ receptors reduced effects of LPS on ERK-1/2 phosphorylation through NO. JWH-015 increased LPS-induced NO release at 30 min, while at 4 h CB₂ receptor stimulation had an inhibitory effect. All the effects of JWH-015 were significantly blocked by the CB₂ receptor antagonist AM 630 and, as the inhibition of CB₂ receptor expression by siRNA abolished the effects of JWH-015, were shown to be mediated specifically by activation of CB₂ receptors.

CONCLUSIONS AND IMPLICATIONS

Our results demonstrate that CB₂ receptor stimulation activated the MAPK pathway, but the presence of a second stimulus blocked MAPK signal transduction, inhibiting pro-inflammatory LPS-induced production of NO. Therefore, CB₂ receptor agonists may promote anti-inflammatory therapeutic responses in activated microglia.     

Disruption of the gene encoding the beta1-subunit of transducin in the Rd4/+ mouse

PURPOSE: The Rd4/+ mouse inherits an autosomal dominant retinal degeneration that cosegregates with a large inversion spanning nearly all of mouse chromosome 4 (Chr 4). This inversion is homozygous lethal. The hypothesis for the study was that disruption of a gene at one of the two breakpoints in the Rd4 chromosome is responsible for the retinal degeneration. The purpose was to identify the disrupted gene. METHODS: Genotyping was performed by PCR and gel electrophoresis. The Rd4/+ phenotype was confirmed by ERG. Fluorescence in situ hybridization (FISH) analysis was performed with bacterial artificial chromosome (BAC) probes. Northern and quantitative PCR procedures were used to evaluate Gnb1 mRNA expression. Protein expression was measured by Western blot. RESULTS: To identify the Rd4 gene defect, the breakpoints were first localized with a testcross and the locus refined by using FISH. Genetic testcross data revealed that the inversion breakpoints are located within a few centimorgans of both the telomeric and centromeric ends of Chr 4. Initial FISH analysis showed the proximal breakpoint of the inversion to be in the centromere itself. Therefore, we focused on the distal breakpoint and found that it lies in the second intron of the gene Gnb1, coding for the transducin beta1-subunit (Tbeta1) protein that is directly involved in the response to light of rod photoreceptors. Before the beginning of retinal degeneration in Rd4/+ retina, the levels of Gnb1 mRNA and Tbeta1 protein are 50% of those in wild-type retina. CONCLUSIONS: The results suggest that disruption of the Gnb1 gene is responsible for Rd4 retinal disease.     

Continent jejunal reservoir dialysis for end-stage renal disease: is it possible?

With limited organs available for renal transplantation in comparison with the number of patients on the waiting list, and with the drawbacks of dialysis, other forms of treatment for end-stage renal disease (ESRD) need to be investigated. We propose that using a reconfigured segment of bowel as a reservoir in which dialysate of various compositions can be instilled to remove metabolic wastes usually handled by the kidney may augment or replace renal function in a uremic patient. We have chosen the jejunum and have documented our preliminary findings using hyperosmotic dialysate along with the unique characteristics of continent jejunal reservoir dialysis (CJRD). With further refinements, CJRD may eventually be offered as an alternative treatment for ESRD.