Chronic pain exacerbates memory impairment and pathology of Aß and tau by upregulating IL-1ß and p-65 signaling in a mouse model of Alzheimer's disease.

BACKGROUND: Chronic pain is linked to cognitive impairment; however, the underlying mechanisms remain unclear. In the present study, we examined these mechanisms in a well-established mouse model of Alzheimer's disease (AD). METHODS: Neuropathic pain was modeled in 5-month-old transgenic APPswe/PS1dE9 (APP/PS1) mice by partial ligation of the sciatic nerve on the left side, and chronic inflammatory pain was modeled in another group of APP/PS1 mice by injecting them with complete Freund's adjuvant on the plantar surface of the left hind paw. Six weeks after molding, the animals were tested to assess pain threshold (von Frey filament), learning, memory (novel object recognition, Morris water maze, Y-maze, and passive avoidance), and depression-like symptoms (sucrose preference, tail suspension, and forced swimming). After behavioral testing, mice were sacrificed and the levels of p65, amyloid-ß (residues 1-42) and phospho-tau in the hippocampus and cerebral cortex were assayed using western blotting, while interleukin (IL)-1ß levels were measured by enzyme-linked immunosorbent assay. RESULTS: Animals subjected to either type of chronic pain showed lower pain thresholds, more severe deficits in learning and memory, and stronger depression-like symptoms than the corresponding control animals. Either type of chronic pain was associated with upregulation of p65, amyloid-ß (1-42), and IL-1ß in the hippocampus and cerebral cortex, as well as higher levels of phosphorylated tau. CONCLUSIONS: Chronic pain may exacerbate cognitive deficits and depression-like symptoms in APP/PS1 mice by worsening pathology related to amyloid-ß and tau and by upregulating signaling involving IL-1ß and p65.

Baicalin attenuates amyloid ß oligomers induced memory deficits and mitochondria fragmentation through regulation of PDE-PKA-Drp1 signalling.

RATIONALE: Mitochondrial fragmentation contributes to the initiation of Alzheimer's disease (AD) pathology. Baicalin plays a significant role in rescuing mitochondrial dysfunction. However, the effect of baicalin treatment on the modulation of mitochondrial fragmentation has not yet been assessed. OBJECTIVES: The present study was designed to evaluate the effect of baicalin on memory and understand its mechanism of action. RESULTS: Baicalin treatment significantly reversed the altered learning and memory behaviours in AD mouse model. We found that baicalin treatment significantly improved the levels of microtubule association protein-2 and enhanced the expression of synaptophysin and postsynaptic density protein 95 (PSD95). Moreover, treatment with baicalin reversed amyloid-ß oligomer (AßO)-induced abnormalities in the succinate dehydrogenase complex iron sulphur subunit B (SDHB) and cytochrome c oxidase components I (COXI) and mitochondrial fragmentation in the hippocampus. Further, we found that baicalin decreased the PDE4 levels and upregulated the levels of phosphorylated Ser157 site of vasodilator-stimulated phosphoprotein (pVASPs157) and phosphorylated Ser637 site of mitochondrial dynamin-related protein 1 (pDrp1S637). Moreover, in AßO-treated HT-22 cells, H89 inhibited the effect of baicalin on PSD95, mitochondrial fragmentation, SDHB and COXI, PDE4, pVASPs157, and pDrp1S637. CONCLUSION: The effect of baicalin on memory improvement may be due to improved synaptic plasticity, mitochondrial fragmentation, and rescue of dysfunction via the inhibition of PDE4, which leads to activation of pDrp1S637 in the AßO-induced model.

Inhibition of phosphodiesterase-4 in the spinal dorsal horn ameliorates neuropathic pain via cAMP-cytokine-Cx43 signaling in mice.

BACKGROUND: The spinal phosphodiesterase-4 (PDE4) plays an important role in chronic pain. Inhibition of PDE4, an enzyme catalyzing the hydrolysis of cyclic adenosine monophosphate AMP (cAMP), produces potent antinociceptive activity. However, the antinociceptive mechanism remains largely unknown. Connexin43 (Cx43), a gap junction protein, has been shown to be involved in controlling pain transduction at the spinal level; restoration of Cx43 expression in spinal astrocytes to the normal levels reduces nerve injury-induced pain. Here, we evaluate the novel mechanisms involving spinal cAMP-Cx43 signaling by which PDE4 inhibitors produce antinociceptive activity. METHODS: First, we determined the effect of PDE4 inhibitors rolipram and roflumilast on partial sciatic nerve ligation (PSNL)-induced mechanical hypersensitivity. Next, we observed the role of cAMP-Cx43 signaling in the effect of PDE4 inhibitors on PSNL-induced mechanical hypersensitivity. RESULTS: Single or repeated, intraperitoneal or intrathecal administration of rolipram or roflumilast significantly reduced mechanical hypersensitivity in mice following PSNL. In addition, repeated intrathecal treatment with either of PDE4 inhibitors reduced PSNL-induced downregulation of cAMP and Cx43, and upregulation of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1ß. Furthermore, the antinociceptive effects of PDE4 inhibitors were attenuated by the protein kinase A (PKA) inhibitor H89, TNF-α, or Cx43 antagonist carbenoxolone. Finally, PSNL-induced upregulation of PDE4B and PDE4D, especially the PDE4B subtype, was reduced by treatment with either of the PDE4 inhibitors. CONCLUSIONS: The results suggest that the antinociceptive effect of PDE4 inhibitors is contributed by increasing Cx43 expression via cAMP-PKA-cytokine signaling in the spinal dorsal horn.

Attenuation of ethanol abstinence-induced anxiety- and depressive-like behavior by the phosphodiesterase-4 inhibitor rolipram in rodents.

RATIONALE: Withdrawal symptoms stand as a core feature of alcohol dependence. Our previous results have shown that inhibition of phosphodiesterase-4 (PDE4) decreased ethanol seeking and drinking in alcohol-preferring rodents. However, little is known about whether PDE4 is involved in ethanol abstinence-related behavior. OBJECTIVE: The objective of this study was to characterize the role of PDE4 in the development of anxiety- and depressive-like behavior induced by abstinence from ethanol exposure in different animal models. METHODS: Using three rodent models of ethanol abstinence, we examined the effects of rolipram, a prototypical, selective PDE4 inhibitor, on (1) anxiety-like behavior induced by repeated ethanol abstinence in the elevated plus maze test in fawn-hooded (FH/Wjd) rats, (2) anxiety-like behavior in the open-field test and light-dark transition test following acute ethanol abstinence in C57BL/6J mice, and (3) anxiety- and depressive-like behavior induced by protracted ethanol abstinence in the elevated plus maze, forced-swim, and tail-suspension tests in C57BL/6J mice. RESULTS: Pretreatment with rolipram (0.1 or 0.2 mg/kg) significantly increased entries and time spent in the open arms of the elevated plus maze test in rats with repeated ethanol abstinence. Similarly, in mice with acute ethanol abstinence, administration of rolipram (0.25 or 0.5 mg/kg) dose-dependently increased the crossings in the central zone of the open-field test and duration and transitions on the light side of the light-dark transition test, suggesting anxiolytic-like effects of rolipram. Consistent with these, chronic treatment with rolipram (0.1, 0.3, or 1.0 mg/kg) increased entries in the open arms of the elevated plus maze test; it also reduced the increased duration of immobility in both the forced-swim and tail-suspension tests in mice after protracted ethanol abstinence, suggesting antidepressant-like effects of rolipram. CONCLUSIONS: These results provide the first demonstration for that PDE4 plays a role in modulating the development of negative emotional reactions associated with ethanol abstinence, including anxiety and depression. PDE4 inhibitors may be a novel class of drugs for treatment of alcoholism.