The thermal cis-to-trans isomerization rate of various azobenzenes was followed by means of spectrophotometric and flash photolysis techniques. For para-donor/para′-acceptor-substituted azobenzenes such as 4-nitro-4′-dimethylaminoazobenzene, the rate was distinctly accelerated, the activation energy decreasing with the increase in the polarity of solvents. Introduction of substituents in para positions with respect to azo group increased the rate irrespective of substituent. The effect is additive and a Hammett-type equation holds. For 4-dimethylamino-and 4-nitroazobenzenes, while the 2-methyl group accelerated the rate, the 2′-methyl group did not. The results suggest that the isomerization proceeds via inversion mechanism and the rate is controlled mainly by the resonance stabilization in the coplanar transition state. The inversion center for asymmetric azobenzenes is discussed.
Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.
Activation of P2X 3 and P2X 2/3 receptors (P2X 3 R/P2X 2/3 R), ionotropic ATP receptor subtypes, in primary sensory neurons is involved in neuropathic pain, a debilitating chronic pain that occurs after peripheral nerve injury. However, the underlying mechanisms remain unknown. We investigated the role of cytosolic phospholipase A 2 (cPLA 2 ) as a downstream molecule that mediates the P2X 3 R/P2X 2/3 R-dependent neuropathic pain. We found that applying ATP to cultured dorsal root ganglion (DRG) neurons increased the level of Ser505-phosphorylated cPLA 2 and caused translocation of Ser505-phosphorylated cPLA 2 to the plasma membrane. The ATP-induced cPLA 2 activation was inhibited by a selective antagonist of P2X 3 R/P2X 2/3 R and by a selective inhibitor of cPLA 2 . In the DRG in vivo, the number of cPLA 2 -activated neurons was strikingly increased after peripheral nerve injury but not after peripheral inflammation produced by complete Freund's adjuvant. Pharmacological blockade of P2X 3 R/P2X 2/3 R reversed the nerve injury-induced cPLA 2 activation in DRG neurons. Moreover, administering the cPLA 2 inhibitor near the DRG suppressed nerve injury-induced tactile allodynia, a hallmark of neuropathic pain. Our results suggest that P2X 3 R/P2X 2/3 R-dependent cPLA 2 activity in primary sensory neurons is a key event in neuropathic pain and that cPLA 2 might be a potential target for treating neuropathic pain.
BackgroundNeuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A2 (cPLA2) in injured dorsal root ganglion (DRG) neurons that contribute to tactile allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA2 activation to produce tactile allodynia remain to be determined.Principal FindingsHere we provide evidence that platelet-activating factor (PAF) is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs) reduced the development and expression of tactile allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced tactile allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of naïve rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFα and IL-1β, both of which were inhibited by pretreatment with a PAFR antagonist.ConclusionsOur results indicate that the PAF/PAFR system has an important role in production of TNFα and IL-1β in the DRG and tactile allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.
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