are often taken chronically, such drugs should feature a good benefit-risk profile and be devoid of long-term safety concerns. However, studies like the one published by Yoriki et al. in this issue of Journal of Gastroenterology and Hepatology are important because they create new conceptual approaches to developing novel therapies that are based on insights into the mechanisms underlying NSAID-induced enteropathy. References 1 Bjarnason I. Gastrointestinal safety of NSAIDs and over-the-counter analgesics. Int. J. Clin. Pract. 2013; 67 (Suppl. 178): 37-42. 2 Wallace JL. NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies. Br. J. Clin. Pharmacol. 2012; 165: 67-74. 3 Boelsterli UA, Redinbo MR, Saitta K. Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies. Toxicol. Sci. 2012. doi: 10.1093/toxsci/kfs310. 4 LoGuidice A, Ramirez-Alcantara V, Proli A, Gavillet B, Boelsterli UA. Pharmacologic targeting or genetic deletion of mitochondrial cyclophilin D protects from NSAID-induced small intestinal ulceration in mice. Toxicol. Sci. 2010; 118: 276-85. 5 Ramirez-Alcantara V, LoGuidice A, Boelsterli UA. Protection from diclofenac-induced small intestinal injury by the JNK inhibitor SP600125 in a mouse model of NSAID-associated enteropathy. Am. J. Physiol. (Gastrointest. Liver Physiol.) 2009; 297: G990-8. 6 Zhu Y, Zhang QY. Role of intestinal cytochrome P450 enzymes in diclofenac-induced toxicity in the small intestine. J. Pharmacol. Exp. Ther. 2012; 343: 362-70. 7 Yamada S, Naito Y, Takagi T et al. Rebamipide ameliorates indomethacin-induced small intestinal injury in rats via the inhibition of matrix metalloproteases activity. J. Gastroenterol. Hepatol. 2012; 27: 1816-24. 8 Somasundaram S, Rafi S, Hayllar J et al. Mitochondrial damage: a possible mechanism of the "topical" phase of NSAID induced injury to the rat intestine. Gut 1997; 41: 344-53. 9 Yoriki H, Naito Y, Takagi T et al. Hemin ameliorates indomethacin-induced small intestinal injury in mice through the induction of heme oxygenase-1. J. Gastroenterol. Hepatol. 2013; 28: 632-8. 10 Vile GF, Basu-Modak S, Waltner C, Tyrrell RM. Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts. 278: L312-9. 12 Cantoni L, Valaperta R, Ponsoda X et al. Induction of hepatic heme oxygenase-1 by diclofenac in rodents: role of oxidative stress and cytochrome P-450 activity. J. Hepatol. 2003; 38: 776-83. 13 Siegert SWK, Holt RJ. Physicochemical properties, pharmacokinetics, and pharmacodynamics of intravenous hematin: a literature review. Adv. Ther. 2008; 25: 842-57. 14 Wallace BD, Wang H, Lane KT et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 2010; 330: 831-5. 15 LoGuidice A, Wallace BD, Bendel L, Redinbo MR, Boelsterli UA. Pharmacologic targeting of bacterial b-glucuronidase alleviates nonsteroidal anti-inflammatory drug-induced enteropathy in mice.

We have previously demonstrated that a small molecule inhibitor of bacterial β-glucuronidase (Inh-1; [1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea]) protected mice against diclofenac (DCF)-induced enteropathy. Here we report that Inh-1 was equally protective against small intestinal injury induced by other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin (10 mg/kg, ip) and ketoprofen (100 mg/kg, ip).Inh-1 provided complete protection if given prior to DCF (60 mg/kg, ip), and partial protection if administered 3-h post-DCF, suggesting that the temporal window of mucosal protection can be extended for drugs undergoing extensive enterohepatic circulation.Pharmacokinetic analysis of Inh-1 revealed an absolute bioavailability (F) of 21% and a short t1/2 of <1 h. This low F was shown to be due to hepatic first-pass metabolism, as confirmed with the pan-CYP inhibitor, 1-aminobenzotriazole.Using the fluorescent probe 5 (and 6)-carboxy-2′,7′-dichlorofluorescein, we demonstrated that Inh-1 did not interfere with hepatobiliary export of glucuronides in gall bladder-cannulated mice.These data are compatible with the hypothesis that pharmacological inhibition of bacterial β-glucuronidase-mediated cleavage of NSAID glucuronides in the small intestinal lumen can protect against NSAID-induced enteropathy caused by locally high concentrations of NSAID aglycones.

Astrocytes are well known to play critical roles in the development and maintenance of the central nervous system (CNS). Moreover, recent reports indicate that these cells are heterogeneous with respect to the molecules they express and the functions they exhibit in the quiescent or activated state. Because astrocytes also contribute to pathology, promising new results raise the possibility of manipulating specific astroglial populations for therapeutic roles. In this mini-review, we highlight the function of metabotropic glutamate receptors (mGluRs), in particular mGluR3 and mGluR5, in reactive astrocytes and relate these to three degenerative CNS diseases: multiple sclerosis, Alzheimer's disease and Amyotrophic Lateral Sclerosis. Previous studies demonstrate that effects of these receptors may be beneficial, but this varies depending on the subtype of receptor, the state of the astrocytes, and the specific disease to which they are exposed. Elucidating the role of mGluRs on astrocytes at specific times during development and disease will provide novel insights in understanding how to best use these to serve as therapeutic targets.

It is well recognized that astrocytes can produce factors known to affect the myelination process. One such factor, brain‐derived neurotrophic factor (BDNF), can enhance the differentiation of oligodendrocyte lineage cells following a demyelinating lesion. Our previous work indicated that enhancing astrocyte‐derived BDNF via injection of a general agonist of Group I/II metabotropic glutamate receptors (mGluRs) into the lesion increased myelin proteins in the cuprizone model of demyelination after 4 hr. To determine if this observation has potential therapeutic significance, we now use a more specific mGluR agonist, 2‐chloro‐5‐hydroxyphenylglycine (CHPG), which binds to mGluR5, to examine effects on myelination through the clinically relevant approach of a peripheral injection. In initial studies, intraperitoneal injection of CHPG resulted in an increase in myelin proteins within the lesioned corpus callosum. These effects were blocked when either BDNF or the CHPG receptor, mGluR5, was deleted from glial fibrillary acidic protein (GFAP)+ astrocytes or when the BDNF receptor, tropomyosin receptor kinase B (TrkB), was deleted from proteolipid protein (PLP)+ oligodendrocytes. Moreover, injection of CHPG over 2 weeks not only elevated BDNF and myelin proteins, but also enhanced myelination and reversed behavioral deficits. Interestingly, effects on myelin and myelin proteins were not seen in the control animals, indicating that a lesion is critical in eliciting effects. Taken together, the data suggest that the mGluR agonist CHPG may be a potential therapeutic strategy for treating demyelinating diseases and that it works by enhancing the release of BDNF from astrocytes.