Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 versus monotherapy was investigated in an APP/PS1 mouse model of AD. Our data demonstrate that both combination treatment and monotherapy attenuated brain Aβ and improved the nesting behavioral deficit to varying degrees. Importantly, the combination treatment group had the lowest Aβ levels, and insoluble forms of Aβ were reduced most effectively. The nesting performance of APP/PS1 mice receiving combination treatment was better than that of other APP/PS1 groups. Further findings indicate that enhanced microglial Aβ phagocytosis and lower levels of proinflammatory cytokines were concurrent with the aforementioned effects of NP106 in combination with TML-6. Intriguingly, combination treatment also normalized the gut microbiota of APP/PS1 mice to levels resembling the wild-type control. Taken together, combination treatment outperformed NP106 or TML-6 monotherapy in ameliorating Aβ pathology and the nesting behavioral deficit in APP/PS1 mice. The superior effect might result from a more potent modulation of microglial function, cerebral inflammation, and the gut microbiota. This innovative treatment paradigm confers a new avenue to develop more efficacious AD treatments.

<p>Granulocyte colony stimulating factor (GCSF) is an endogenous growth factor that can stimulate granulocyte formation and is used widely in hematogenous disease without significant clinical side effects. Several clinical and animal studies had showed that both a single high-dose and repeated low-dose systemic GCSF treatment can attenuate neuropathic pain after central or peripheral nerve injury. GCSF treatment can recruit more opioid containing neutrophils to injured tissue, up-regulate opioid receptors (mu opioid receptor) on the injured nerve, which decreased nociceptive signals from injured nerve to the spinal dorsal horn. Thereafter, activated microglia, increased phosphorylated-p38 (p-p38) and pro-inflammatory cytokines on the spinal dorsal horn are suppressed, which further attenuated neuropathic pain. The systemic GCSF administration may avoid the addiction side effect induced by repeated exogenous opioid exposure and provide a new therapeutic strategy to treat neuropathic pain.</p>

BackgroundHonokiol, a cell-permeable phenolic compound derived from the bark of magnolia trees and present in Asian herbal teas, has a unique array of pharmacological actions, including the inhibition of multiple autonomic responses. We determined the effects of honokiol on calcium signaling underlying transmission mediated by human M3 muscarinic receptors expressed in Chinese hamster ovary (CHO) cells. Receptor binding was determined in radiolabelled ligand binding assays; changes in intracellular calcium concentrations were determined using a fura-2 ratiometric imaging protocol; cytotoxicity was determined using a dye reduction assay.ResultsHonokiol had a potent (EC50 ≈ 5 μmol/l) inhibitory effect on store operated calcium entry (SOCE) that was induced by activation of the M3 receptors. This effect was specific, rapid and partially reversible, and was seen at concentrations not associated with cytotoxicity, inhibition of IP3 receptor-mediated calcium release, depletion of ER calcium stores, or disruption of M3 receptor binding.ConclusionsIt is likely that an inhibition of SOCE contributes to honokiol disruption of parasympathetic motor functions, as well as many of its beneficial pharmacological properties.

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Background Chronic neuro‐inflammation leading to excessive neuronal damages predates the presence of clinical manifestations of Alzheimer’s disease (AD) by many years. Due to the complex pathogenesis of AD, a multi‐target regimen using a combination therapy is proposed to be essential to the effectiveness of AD therapy. Method An innovative combination therapy using a newly developed multi‐functional Aβ antibody (NP106) and a novel curcumin derivative (TML‐6) was applied to treat APP/PS1 mice. To investigate whether synergistic effects of combination therapy on reducing AD‐like pathology in APP/PS1 mice alter fecal microbiome, high‐throughput 16S rRNA sequencing was performed. Result Here, we demonstrate that monotherapy with either weekly intraperitoneal injection of low‐dose NP106 or TML‐6‐supplemented diet for four months showed beneficial effects on counteracting AD‐like pathology in APP/PS1 mice, while combination therapy using these two drugs outperformed monotherapy and exerted synergistic effects on improving behavioral abnormality and reducing cerebral Aβ accumulation. Data from microbiome indicate that the gut bacterial community structure of APP/PS1 mice was different from those of wt littermates. Intriguingly, relative abundant genera of APP/PS1 mice can be restored by either monotherapy or combination therapy to levels similar to wt littermates, indicating that these treatments possessed prebiotic effects against gut dysbiosis. Importantly, analyses of samples diversity further reveal that combination therapy might lead to better normalization of microbiota. Conclusion Combination therapy exerted synergistic effects on attenuating AD‐like pathological features and behavioral deficits in APP/PS1 mice. Furthermore, the synergistic effects of combination therapy were concurrent with the normalization of gut microbiota.

Cell‐permeable biphenols, such as honokiol, present in herbal teas, inhibit autonomic responses. The effects of biphenols on calcium signaling activated by human M3 muscarinic receptors was studied in Chinese hamster ovary (CHO) cells. Receptor binding was determined by radiolabelled ligand binding; intracellular calcium concentrations were determined using a fura‐2 ratiometric imaging protocol; cytotoxicity was determined using a dye reduction assay. Activation of M3 muscarinic receptors with carbachol induced a biphasic increase in [Ca2+]i: an initial, IP3‐ mediated release of Ca2+ from endoplasmic reticulum stores followed by a sustained phase of steady Ca2+ entry (i.e., store operated calcium entry, SOCE). Biphneols had potent (EC50 ≈ 5 μM) inhibitory effects on SOCE that was induced by the activation of the M3 receptor. SOCE was also examined by acute exposure to thapsigarin (2 μM) in a calcium‐free medium, followed by reintroduction of calcium. Again, SOCE was severely depressed by biphenols. The effect of honokiol on SOCE was specific, rapid and partially reversible, and was seen at concentrations not associated with cytotoxicity, inhibition of IP3 receptor‐mediated calcium release, or depletion of ER calcium stores. Moreover, biphenols did not disrupt the ligand binding properties of M3 receptors. An inhibition of SOCE probably contributes to biphenol disruption of parasympathetic functions.

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