Neural stem cell (NSC) transplantation has been investigated as a means to reconstitute the damaged brain after stroke. In this study, however, we investigated the effect on acute cerebral and peripheral inflammation after intracerebral haemorrhage (ICH). NSCs (H1 clone) from fetal human brain were injected intravenously (NSCs-iv, 5 million cells) or intracerebrally (NSCs-ic, 1 million cells) at 2 or 24 h after collagenase-induced ICH in a rat model. Only NSCs-iv-2 h resulted in fewer initial neurologic deteriorations and reduced brain oedema formation, inflammatory infiltrations (OX-42, myeloperoxidase) and apoptosis (activated caspase-3, TUNEL) compared to the vehicle-injected control animals. Rat neurosphere-iv-2 h, but not human fibroblast-iv-2 h, also reduced the brain oedema and the initial neurologic deficits. Human NSCs-iv-2 h also attenuated both cerebral and splenic activations of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-kappaB). However, we observed only a few stem cells in brain sections of the NSCs-iv-2 h group; in the main, they were detected in marginal zone of spleens. To investigate whether NSCs interact with spleen to reduce cerebral inflammation, we performed a splenectomy prior to ICH induction, which eliminated the effect of NSCs-iv-2 h transplantation on brain water content and inflammatory infiltrations. NSCs also inhibited in vitro macrophage activations after lipopolysaccharide stimulation in a cell-to-cell contact dependent manner. In summary, early intravenous NSC injection displayed anti-inflammatory functionality that promoted neuroprotection, mainly by interrupting splenic inflammatory responses after ICH.

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Erythropoietin (EPO), a pleiotropic cytokine involved in erythropoiesis, is tissue-protective in ischemic, traumatic, toxic and inflammatory injuries. In this study, we investigated the effect of EPO in experimental intracerebral hemorrhage (ICH). Two hours after inducing ICH via the stereotaxic infusion of collagenase, recombinant human EPO (500 or 5000 IU/kg, ICH + EPO group) or PBS (ICH + vehicle group) was administered intraperitoneally, then once daily afterwards for 1 or 3 days. ICH + EPO showed the better functional recovery in both rotarod and modified limb placing tests. The brain water content was decreased in ICH + EPO dose-dependently, as compared with ICH + vehicle. The effect of EPO on the brain water content was inhibited by N(omega)-Nitro-Larginine methyl ester hydrochloride (L-NAME, 10 mg/kg).Mean hemorrhage volume was also decreased in ICH + EPO. EPO reduced the numbers of TUNEL +, myeloperoxidase + or OX-42 + cells in the perihematomal area. In addition, EPO reduced the mRNA level of TNF-a, Fas and Fas-L, as well as the activities of caspase-8, 9 and 3. EPO treatment showed up-regulations of endothelial nitric oxide synthase (eNOS) and p-eNOS, pAkt, pSTAT3 and pERK levels. These data suggests that EPO treatment in ICH induces better functional recovery with reducing perihematomal inflammation and apoptosis, coupled with activations of eNOS, STAT3 and ERK. Keywords: apoptosis, endothelial nitric oxide synthase, extracellular signal-regulated kinase, erythropoietin, inflammation, intracerebral hemorrhage, STAT3. J. Neurochem. (2006Neurochem. ( ) 96, 1728Neurochem. ( -1739 Intracerebral hemorrhage (ICH) represents 15% of all strokes in Western populations and a higher proportion (20-30%) in Asian and black populations, and is the least treatable form of stroke with high mortality and morbidity (Qureshi et al. 2001). Nevertheless, supportive care or invasive neurosurgical evacuation of hematoma in selective patients is all that can be done (Mendelow et al. 2005). However, a controlled trial indicates that ICH patients show no overall benefit from early surgery when compared with medical treatment (Mendelow et al. 2005 These authors contributed equally to this study.Abbreviations used: EPO, erythropoietin; ICH, intracerebral hemorrhage; TUNEL, terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling; MPO, myeloperoxidase, STAT, signal transducers and activators of transcription; NOS, nitric oxide synthase; TNF, tumor necrosis factor; MLPT, modified limb placing test; BDNF, brainderived neurotrophic factor; ROS, reactive oxygen species; MCP-1, monocyte chemoattractant protein-1; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; NFjB, nuclear factor-b; JAK-2, Janus kinase-2; L-NAME, N(omega)-Nitro-L-arginine methyl ester hydrochloride; ERK, extracellular signal-regulated kinase.Journal of Neurochemistry, 2006Neurochemistry, , 96, 1728Neurochemistry, -1739Neurochemistry, doi:10.1111Neurochemistry, /j.1471Neurochemistry, -4159.2006 (Broderick e...

Despite its clinical importance, the mechanisms that mediate or generate itch are poorly defined. The identification of pruritic compounds offers insight into understanding the molecular and cellular basis of itch. Imiquimod (IQ) is an agonist of Toll-like receptor 7 (TLR7) used to treat various infectious skin diseases such as genital warts, keratosis, and basal cell carcinoma. Itch is reportedly one of the major side effects developed during IQ treatments. We found that IQ acts as a potent itch-evoking compound (pruritogen) in mice via direct excitation of sensory neurons. Combined studies of scratching behavior, patch-clamp recording, and Ca 2+ response revealed the existence of a unique intracellular mechanism, which is independent of TLR7 as well as different from the mechanisms exploited by other well-characterized pruritogens. Nevertheless, as for other pruritogens, IQ requires the presence of transient receptor potential vanilloid 1 (TRPV1)-expressing neurons for itchassociated responses. Our data provide evidence supporting the hypothesis that there is a specific subset of TRPV1-expressing neurons that is equipped with diverse intracellular mechanisms that respond to histamine, chloroquine, and IQ.