SUMMARY Metabolites in the kynurenine pathway of tryptophan degradation are thought to play an important role in neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease. Metabolites that cause glutamate receptor-mediated excitotoxicity and free radical formation are elevated in the blood and vulnerable brain regions in these diseases, while levels of the neuroprotective metabolite kynurenic acid are often decreased. Here we describe the synthesis and characterization of JM6, a novel small-molecule pro-drug inhibitor of kynurenine 3-monooxygenase (KMO). JM6 raises kynurenic acid and reduces extracellular glutamate in the brain after chronic oral administration by inhibiting KMO in blood. In a transgenic mouse model of Alzheimer’s disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extended life span, prevented synaptic loss, and decreased microglial activation in a mouse model of Huntington’s disease. These findings support a critical link between blood cells and neurodegeneration that is mediated by KMO and the kynurenine pathway.

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We describe here the pha macological properties of RP 67580 {(3aR,7aR)-7,7-diphenyl-2-[1-imlno-2-(2- To understand how SP acts in the central and peripheral nervous system, various agonists (either endogenous TKs or their analogues) were used to identify three types of SP receptors, which were called neurokinin receptors types 1, 2, and 3 (NK1, NK2, and NK3 receptors, respectively). All three receptors have been cloned and sequenced (7-9). SP binds most strongly to the NK1 receptors, whereas neurokinin A (NKA) and neurokinin B (NKB), two other mammalian TKs, preferentially bind to NK2 and NK3 receptors, respectively (for review, see refs. 10 and 11). However, it was only with the identification of antagonists that specifically block the actions of SP that the physiological and pathological functions of SP could be investigated. In the last decade, various SP antagonists, which are, in fact, chemical analogues of SP, have been described (12). However, these peptides have major disadvantages: they are metabolically unstable, only weakly active, and not selective with respect to the different receptor subtypes (for review, see refs. 12 and 13). More recently, a nonpeptide SP antagonist was described but its antinoceptive properties were not reported (14).The present report describes the binding and pharmacological properties of RP 67580, a potent nonpeptide SP antagonist derived from the perhydroisoindole chemical series and selective for the NK1 receptor. Its chemical name is (3aR, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)-ethyl] perhydroisoindol-4-one.The undecapeptide substance P (SP), first isolated in 1931 from extracts of horse brain and intestine (1) Abbreviations: SP, substance P; NK, neurokinin; TK, tachykinin. 10208The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Huntington disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. Previous studies have proposed that activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1) may be of therapeutic benefit. However, the effect of disease progression on the HSR and the therapeutic potential of this pathway are currently unknown. Here, we used a brain-penetrating HSP90 inhibitor and physiological, molecular, and behavioral readouts to demonstrate that pharmacological activation of HSF1 improves huntingtin aggregate load, motor performance, and other HD-related phenotypes in the R6/2 mouse model of HD. However, the beneficial effects of this treatment were transient and diminished with disease progression. Molecular analyses to understand the transient nature of these effects revealed altered chromatin architecture, reduced HSF1 binding, and impaired HSR accompanied disease progression in both the R6/2 transgenic and HdhQ150 knockin mouse models of HD. Taken together, our findings reveal that the HSR, a major inducible regulator of protein homeostasis and longevity, is disrupted in HD. Consequently, pharmacological induction of HSF1 as a therapeutic approach to HD is more complex than was previously anticipated.