BackgroundTraditional Chinese medicinal herbs Cortex Moutan and Radix Salviae Milthiorrhizaeare are prescribed together for their putative cardioprotective effects in clinical practice. However, the rationale of the combined use remains unclear. The present study was designed to investigate the cardioprotective effects of paeonol and danshensu (representative active ingredient of Cortex Moutan and Radix Salviae Milthiorrhizae, respectively) on isoproterenol-induced myocardial infarction in rats and its underlying mechanisms.MethodologyPaeonol (80 mg kg−1) and danshensu (160 mg kg−1) were administered orally to Sprague Dawley rats in individual or in combination for 21 days. At the end of this period, rats were administered isoproterenol (85 mg kg−1) subcutaneously to induce myocardial injury. After induction, rats were anaesthetized with pentobarbital sodium (35 mg kg−1) to record electrocardiogram, then sacrificed and biochemical assays of the heart tissues were performed.Principal FindingsInduction of rats with isoproterenol resulted in a marked (P<0.001) elevation in ST-segment, infarct size, level of serum marker enzymes (CK-MB, LDH, AST and ALT), cTnI, TBARS, protein expression of Bax and Caspase-3 and a significant decrease in the activities of endogenous antioxidants (SOD, CAT, GPx, GR, and GST) and protein expression of Bcl-2. Pretreatment with paeonol and danshensu combination showed a significant (P<0.001) decrease in ST-segment elevation, infarct size, cTnI, TBARS, protein expression of Bax and Caspase-3 and a significant increase in the activities of endogenous antioxidants and protein expression of Bcl-2 and Nrf2 when compared with individual treated groups.Conclusions/SignificanceThis study demonstrates the cardioprotective effect of paeonol and danshensu combination on isoproterenol-induced myocardial infarction in rats. The mechanism might be associated with the enhancement of antioxidant defense system through activating of Nrf2 signaling and anti-apoptosis through regulating Bax, Bcl-2 and Caspase-3. It could provide experimental evidence to support the rationality of combinatorial use of traditional Chinese medicine in clinical practice.

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Abnormal activation of calpain is implicated in synaptic dysfunction and participates in neuronal death in Alzheimer disease (AD) and other neurological disorders. Pharmacological inhibition of calpain has been shown to improve memory and synaptic transmission in the mouse model of AD. However, the role and mechanism of calpain in AD progression remain elusive. Here we demonstrate a role of calpain in the neuropathology in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, an established mouse model of AD. We found that overexpression of endogenous calpain inhibitor calpastatin (CAST) under the control of the calcium/calmodulindependent protein kinase II promoter in APP/PS1 mice caused a remarkable decrease of amyloid plaque burdens and prevented Tau phosphorylation and the loss of synapses. Furthermore, CAST overexpression prevented the decrease in the phosphorylation of the memory-related molecules CREB and ERK in the brain of APP/PS1 mice and improved spatial learning and memory. Interestingly, treatment of cultured primary neurons with amyloid-␤ (A␤) peptides caused an increase in the level of ␤-site APP-cleaving enzyme 1 (BACE1), the key enzyme responsible for APP processing and A␤ production. This effect was inhibited by CAST overexpression. Consistently, overexpression of calpain in heterologous APP expressing cells up-regulated the level of BACE1 and increased A␤ production. Finally, CAST transgene prevented the increase of BACE1 in APP/PS1 mice. Thus, calpain activation plays an important role in APP processing and plaque formation, probably by regulating the expression of BACE1. Aggregation of amyloid-␤ (A␤)3 peptides into compact plaques is a characteristic feature in the pathogenesis of Alzheimer disease (AD) (1, 2). Recently, it is suggested that soluble A␤ oligomers, in the process of aggregation, adversely affect synaptic structure and plasticity (2-9). A␤ peptides are generated in neurons by the sequential proteolytic cleavage of the transmembrane glycoprotein amyloid precursor protein (APP) that is cleaved initially by ␤-site APP-cleaving enzyme 1 (BACE1, also known as ␤-secretase) and subsequently by ␥-secretase, whose activity is associated with a presenilin (PS)-containing macromolecular complex (10 -12), in the transmembrane region of APP (13,14). Thus, BACE1 has been proposed to be a therapeutic target for AD (15).Calpains are a family of calcium-activated intracellular cysteine proteases that are involved in many physiological events including long term potentiation (16 -18) or neurotoxic insults ranging from ischemia to Alzheimer disease (19 -21). Inhibition of calpain by synthetic inhibitors exerts neuroprotection in various models of brain injuries, such as ischemia or excitotoxicity-induced neuronal death (22-24). Interestingly, A␤ aggregation is associated with neuronal and astrocytic calcium dysregulation (25-27). Treatment of cultured cortical neurons with A␤ oligomers caused calcium influx and subsequently calpain activation (21).A number of proteins hav...

Dendrite morphogenesis is regulated by neuronal activity or neurotrophins, which may function by activating intrinsic signaling proteins, including Rho family GTPases. Here we report that activity-and brain-derived neurotrophic factor (BDNF)-dependent dendritic morphogenesis requires activation of geranylgeranyltransferase I (GGT), a prenyltransferase that mediates lipid modification of Rho GTPases. Dendritic arborization in cultured hippocampal neurons was promoted by over-expression of GGT, and reduced by inhibition or down-regulation of GGT. Furthermore, GGT was activated by neuronal depolarization or BDNF, both of which promote dendritic arborization, in cultured hippocampal neurons. Moreover, exploration of a novel environment caused activation of GGT in the mice hippocampus, suggesting that neural activity activates GGT in vivo. Interestingly, GGT was physically associated with tropomyosin-related kinase B (TrkB), the receptor for BDNF, and this association was enhanced by depolarization. Disrupting the GGT-TrkB interaction or down-regulating GGT activity attenuated depolarization-or BDNF-induced dendrite development. Finally, the GGT effect on dendrite arborization was prevented by over-expressing Rac1 with the prenylation site deleted or mutated. Thus depolarization-or BDNF-dependent dendrite development may be mediated by GGT-induced prenylation of Rho GTPases.BDNF ͉ dendrite ͉ neuronal activity ͉ Rac ͉ prenylation D endritic morphogenesis is a critical step for establishing neural circuits. The growth and branching of dendritic arbors are controlled by both external signals and intracellular pathways (1, 2). Neuronal activity and neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3, are known to regulate dendrite development through multiple signaling pathways, leading to cytoskeletal reorganization or gene expression required for dendritic growth (2-7). For example, members of the Rho family of small GTPases, including Rac1, Cdc42, and RhoA, are important for distinct aspects of dendrite development by modulating actin cytoskeleton (8, 9). Activation of Rho A attenuates dendrite growth and branching, whereas activation of Rac1 facilitates dendrite growth (8, 10, 11). Importantly, dendrite growth increased by visual activity requires Rho GTPases (12) and BDNF-dependent dendritic growth may be mediated by Rac1 (13). Thus, Rho GTPase may mediate the effects of BDNF or neuronal activity on dendrite development. However, the mechanism by which BDNF and activity regulate Rho GTPases remains largely unknown.The Rho GTPase cycles between a GTP-bound active state and a GDP-bound inactive state, and this process is regulated by GTPase activating proteins and guanine nucleotide exchange factors (GEFs) (14, 15). Importantly, GTPases need to be translocated from the cytosol to the membrane for their activation (16,17). This is achieved by prenylation, a reaction mainly catalyzed by farnesyltransferase (FT) or geranylgeranyltransferase I (GGT), which acts to covalently couple a lipid m...