Dysfunctional Mitochondrial Bioenergetics and Synaptic Degeneration in Alzheimer Disease.

Synapses are sites of high energy demand which are dependent on high levels of mitochondrial derived adenosine triphosphate. Mitochondria within synaptic structures are key for maintenance of functional neurotransmission and this critical biological process is modulated by energy metabolism, mitochondrial distribution, mitochondrial trafficking, and cellular synaptic calcium flux. Synapse loss is presumed to be an early yet progressive pathological event in Alzheimer disease (AD), resulting in impaired cognitive function and memory loss which is particularly prevalent at later stages of disease. Supporting evidence from AD patients and animal models suggests that pathological mitochondrial dynamics indeed occurs early and is highly associated with synaptic lesions and degeneration in AD neurons. This review comprehensively highlights recent findings that describe how synaptic mitochondria pathology involves dysfunctional trafficking of this organelle, to maladaptive epigenetic contributions affecting mitochondrial function in AD. We further discuss how these negative, dynamic alterations impact synaptic function associated with AD. Finally, this review explores how antioxidant therapeutic approaches targeting mitochondria in AD can further clinical research and basic science investigations to advance our in-depth understanding of the pathogenesis of AD.

Acupuncture decreases ischemia-induced apoptosis and cell proliferation in dentate gyrus of gerbils.

BACKGROUND: Acupuncture has been used for the enhancement of functional recovery from various disorders. In the present study, the effect of acupuncture on the apoptosis and new cell proliferation in the hippocampal dentate gyrus of gerbils (n = 25) following transient global ischemia was investigated. METHODS: To determine the level of apoptosis and cell proliferation, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU) were employed respectively. RESULTS: In the dentate gyrus of ischemic gerbils, the number of both TUNEL- and BrdU-positive cells (66.01 +/- 2.45/mm(2) and 514.38 +/- 44.90/mm(2)) was significantly increased compared to that of the sham-operated gerbils (11.25 +/- 1.85/mm(2) and 111.47 +/- 10.95/mm(2)). Among the acupuncture (ST36, LI4 or non-acupoint) treated groups, ST36 acupoint treated group showed the most potent apoptosis (20.52 +/- 2.40/mm(2)) and proliferation (159.38 +/- 24.05/mm(2)) suppressive effects ( approximately 70% decreases in both apoptosis and cell proliferation). CONCLUSION: These results may suggest that acupuncture treatment alleviates ischemia-induced apoptosis and presents possible therapeutic potentials in the recovery from ischemic cerebral injury.

Analgesic effects by electroacupuncture were decreased in inducible nitric oxide synthase knockout mice.

BACKGROUND: This study was designed to investigate the involvement of inducible nitric oxide synthase (iNOS) in electroacupuncture (EA)-induced analgesia. METHODS: Two and 100 Hz EA stimulation were applied at acupoint ST 36 (Zusanli) in iNOS knockout mice (n = 28). Needles were inserted 5 mm in depth in ST36. After insertion, the needles were fixed in situ with adhesive tape. EA was applied after the basal threshold determination. The EA parameters were set as follows: constant square wave current output (pulse width: 0.6 ms at 2 Hz and 0.2 ms at 100 Hz) and 2 mA intensities. EA was performed for 30 minutes and tail-flick latencies (TFLs) were evaluated every 15 minutes for 1 hour. RESULTS: In 2 Hz EA stimulation, the tail-flick response (TFR) of wild-type mice for durations of 0, 15, 30, 45 and 60 minutes were 2.70 +/- 0.26, 4.19 +/- 0.37, 4.17 +/- 0.34, 3.57 +/- 0.27 and 3.39 +/- 0.32 seconds of TFLs. Meanwhile, iNOS -/- mice showed 4.10 +/- 0.33, 4.77 +/- 0.24, 5.26 +/- 0.30, 4.48 +/- 0.33 and 5.00 +/- 0.41 seconds of TFLs. In 100 Hz EA stimulation, the TFR of wild-type mice were 3.01 +/- 0.24, 4.67 +/- 0.31, 4.76 +/- 0.25, 4.04 +/- 0.45 and 4.26 +/- 0.30 seconds of TFLs. The iNOS -/- mice were 4.33 +/- 0.16, 5.29 +/- 0.28, 5.06 +/- 0.35, 4.52 +/- 0.17 and 4.80 +/- 0.28 seconds of TFLs. Wild-type mice exhibited 63.9% increase in TFL compared to the baseline after 2 Hz EA, whereas the iNOS knockout mice exhibited 32.9% increase in TFL. The TFL after 100 Hz EA showed similar trends: 66.5% increase in TFL in wildtype mice and 18.3% increase in the iNOS knockout mice. CONCLUSION: The present findings suggested that iNOS may play a crucial role in both low- and high-frequency EA-induced analgesic effects.

Effects of Platycodon grandiflorum on lipopolysaccharide-stimulated production of prostaglandin E2, nitric oxide, and interleukin-8 in mouse microglial BV2 cells.

The roots of Platycodon grandiflorum, which belongs to the Campanulaceae family, have been used as a food material and as a traditional Oriental medicine. The effect of P. grandiflorum against lipopolysaccharide (LPS)-stimulated inflammation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, reverse transcription-polymerase chain reaction, prostaglandin E(2 )(PGE(2)) immunoassay, nitric oxide (NO) detection assay, and interleurkin-8 (IL- 8) immunoassay on BV2 microglial cells. The aqueous extract of P. grandiflorum was shown to suppress PGE(2 )synthesis and NO production by inhibiting LPS-stimulated cyclooxygenase (COX)-2 activity and expression of inducible NO synthase (iNOS) mRNAs. In addition, the treatment with P. grandiflorum reduced the LPS-induced IL-8 release. These results suggest that P. grandiflorum inhibits PGE(2) and NO production through its suppression of LPS-induced COX-2 and iNOS expression, and also reduces IL-8 secretion by microglial cells.

Administration of Ginseng radix decreases nitric oxide synthase expression in the hippocampus of streptozotocin-induced diabetic rats.

Nitric oxide (NO) is synthesized from L-arginine by nitric oxide synthase (NOS). Alternation of NOS expression is implicated in the pathogenesis of numerous secondary complications of diabetes. Aqueous extract of Ginseng radix has traditionally been used for the various disorders including diabetes. In this study, the effect of Ginseng radix on the NOS expression in the hippocampus of streptozotocin (STZ)-induced diabetic rats was investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Enhanced NOS expression was detected in the hippocampus of diabetic rats and administration of Ginseng radix suppressed NOS expression. Ginseng radix may aid the treatment of central nervous system complications in diabetes.

Acupuncture decreases neuropeptide Y expression in the hypothalamus of rats with Streptozotocin-induced diabetes.

It has been known that acupuncture has various effects such as analgesia, promotion of homeostasis, improvements in brain circulation, and rectification of internal disorders. Neuropeptide Y (NPY), a 36-amino-acid peptide, is known to increase appetite. In the present study, the effect of acupuncture stimulation at Zusanli (St.36) on NPY expression in the Streptozotocin (STZ)-induced diabetic rats was investigated via immunohistochemistry. Increased NPY expression was detected in both the Arcuate nucleus (ARN) and the Paraventricular nucleus (PVN) of the Hypothalamus in rats with in STZ-induced diabetes. Needling on Zusanli resulted in decreased NPY levels in both the ARN and PVN of diabetic rats. The present study shows that acupuncture suppressed NPY expression in the ARN and PVN of the Hypothalamus in STZ-induced diabetic rats, suggesting the possibility that acupuncture treatment is effective in curbing the hyperphagia of diabetes.

Atractylodes japonica suppresses lipopolysaccharide-stimulated expressions of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 macrophages.

Atractylodes japonica has traditionally been used for the treatment of pain and arthritis. The effect of Atractylodes japonica against lipopolysaccharide-induced inflammation was investigated using reverse transcription-polymerase chain reaction (RT-PCR), nitric oxide detection, and prostaglandin E2 (PGE2) immunoassay in mouse RAW 264.7 macrophages. The aqueous extract of Atractylodes japonica suppressed nitric oxide production and PGE2 synthesis by inhibition of the lipopolysaccharide-stimulated enhancement of inducible nitric oxide synthase and cyclooxygenase-2 mRNAs expressions in RAW 264.7 macrophages. These results suggest that Atractylodes japonica exerts anti-inflammatory and analgesic effects probably by suppression of the inducible nitric oxide synthase and cyclooxygenase-2 expressions.

Aqueous extract of ma huang suppresses neuropeptide Y expression in food-deprived rat hypothalamus.

Ma huang, the dried plant stem of ephedra intermedia Schrenk et C.A., contains an ephedrine-type alkaloid and has been used for weight loss. Neuropeptide Y (NPY), a 36-amino acid peptide, is concentrated in the hypothalamus and stimulates feeding desire. In this study, the effect of ma huang on the expressions of NPY in the hypothalamus of rats was investigated using immunohistochemistry. Food-deprivation enhanced the NPY expression in the hypothalamus. ma huang suppressed the food-deprivation-induced enhancement of NPY expression. Present results suggest that ma huang curbs the food desire by suppressing the NPY expression under food-deprivation conditions.

Protective effect of aqueous extract of Ginseng radix against 1-methyl-4-phenylpyridinium-induced apoptosis in PC12 cells.

Ginseng radix, the root of Panax ginseng C. A. MEYER (Araliaceae), is one of the best-known Oriental medicinal herbs with numerous therapeutic applications. To investigate whether Ginseng radix possesses a protective effect against 1-methyl-4-phenylpyridine (MPP(+))-induced cytotoxicity in neuronal cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, DNA fragmentation assay, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and caspase-3 enzyme assay were performed on PC12 neuronal cells. Cells treated with MPP(+) exhibited various apoptotic features, while cell pretreated with Ginseng radix prior to MPP(+) exposure showed a decrease in the occurrence of apoptotic features. These results suggest that Ginseng radix may exert a protective effect against MPP(+)-induced apoptosis in PC12 cells.

Harpagophytum procumbens suppresses lipopolysaccharide-stimulated expressions of cyclooxygenase-2 and inducible nitric oxide synthase in fibroblast cell line L929.

Harpagophytum procumbens (Pedaliaceae) has been used for the treatment of pain and arthritis. The effect of Harpagophytum procumbens against lipopolysaccharide-induced inflammation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, reverse transcription-polymerase chain reaction, prostaglandin E(2) (PGE(2)) immunoassay, and nitric oxide detection on mouse fibroblast cell line L929. The aqueous extract of Harpagophytum procumbens was shown to suppress PGE(2) synthesis and nitric oxide production by inhibiting lipopolysaccharide-stimulated enhancement of the cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) mRNAs expressions in L929 cells. These results suggest that Harpagophytum procumbens exerts anti-inflammatory and analgesic effects probably by suppressing cyclooxygenase-2 and iNOS expressions.

Protective effect of shenqi-wan against H2O2-induced apoptosis in hippocampal neuronal cells.

The present study investigated whether Shenqi-wan possesses a protective effect against hydrogen peroxide (H2O2)-induced apoptosis of the hippocampal cell line HiB5. Through morphological and biochemical analyses, it was demonstrated that HiB5 cells treated with H2O2 exhibited several apoptotic features, while cells pre-treated with Shenqi-wan prior to H2O2 exposure showed a decrease in the occurrence of apoptosis. In addition, a patch clamp study revealed that Shenqi-wan inhibited profoundly N-methyl-D-aspartic acid (NMDA) receptor-activated ion current in acutely dissociated hippocampal CA1 neurons. These results suggest that Shenqi-wan may exert its protective effect against H2O2-induced apoptosis via inhibition of NMDA receptors in hippocampal neuronal cells.

Acupuncture modulates expressions of nitric oxide synthase and c-Fos in hippocampus after transient global ischemia in gerbils.

The effects of acupuncture on the expressions of nitric oxide synthase (NOS) and c-Fos in the hippocampus of gerbils after transient ischemia were investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry and Fos immunohistochemistry. In animals of the ischemia-induction groups, both common carotid arteries were occluded for 5 minutes. Animals of the acupunctued groups were given acupunctural treatment at Zusanli twice daily for 9 consecutive days. Acupuncture was shown to decrease NADPH-d and c-Fos levels in both the sham-operation group and the ischemia-induction group. These results suggest that acupuncture modulates the expressions of NOS and c-Fos in the hippocampus.

Red ginseng inhibits exercise-induced increase in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in dorsal raphe of rats.

Red ginseng has been used as an ergogenic aid for endurance exercise. In this study, the effect of aqueous extract of Red ginseng on the endurance in treadmill exercise and 5-hydroxytryptamine (serotonin) synthesis and tryptophan hydroxylase expression in the dorsal raphe of rats were studied. Rats receiving Red ginseng showed increased time to exhaustion for treadmill running, and Red ginseng treatment inhibited exercise-induced increases in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe. These results suggest that the suppressive effect of Red ginseng on serotonin level during exercise is a possible ergogenic mechanism of Red ginseng.

Modulation of Chelidonii herba on glycine-activated and glutamate-activated ion currents in rat periaqueductal gray neurons.

BACKGROUND: Chelidonii herba is classified as Papaver somniferum L. Aqueous extract from C. herba is traditionally used for disorders with symptoms like pain, bloating, abdominal cramp after meals. METHODS: Modulation of C. herba on glycine-activated and glutamate-activated ion currents in the acutely dissociated periaqueductal gray (PAG) neurons was investigated by the nystatin-perforated patch-clamp technique. RESULTS: C. herba inhibited glycine-activated ion current and increased glutamate-activated ion current. C. herba-induced inhibition on glycine-activated ion current is implicated in opioid receptors and GTP-binding proteins (G-proteins). Increased glutamate-activated ion current induced by C. herba is linked neither by opioid receptors nor GTP-binding proteins. CONCLUSIONS: Suppressed glycine-induced response and elevated glutamate-induced response by C. herba may increase neuronal excitability in PAG, results in activation of descending pain control system, and this mechanism can be suggested as one of the analgesic actions of C. herba.

Effect of acupuncture on nitric oxide synthase expression in cerebral cortex of streptozotocin-induced diabetic rats.

Effect of acupuncture on the expressions of nitric oxide synthase (NOS) and neuronal NOS (nNOS) in the cerebral cortex of streptozotocin (STZ)-induced diabetic rats was investigated. Animals were divided into four groups; the control group, the nondiabetic and acupunctured group, the STZ-induced-diabetes group, and the STZ-induced diabetic and acupunctured group. To produce the diabetic animal model, a single intraperitoneal injection of STZ (50 mg/kg) was given to each animal; animals of the nondiabetic groups received equivalent amounts of normal saline, also via intraperitoneal injection. From the results, acupuncture was shown to increase the numbers of nicotinamide adenine dinucleotide phosphate-diaphorase-positive and nNOS-positive neurons in STZ-induced diabetic rats. From the present study, it may be suggested that acupuncture modulates NOS and nNOS expressions in the cerebral cortex under diabetic conditions.

Protective effect of Acanthopanax senticosus against ethanol-induced apoptosis of human neuroblastoma cell line SK-N-MC.

The protective effect of Acanthopanax senticosus (AS) against ethanol (EtOH)-induced apoptosis of the human neuroblastoma cell line SK-N-MC was investigated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometric analysis, DNA fragmentation assay, reverse transcription-polymerase chain reaction (RT-PCR), and caspase-3 assay. It was shown that cells treated with EtOH exhibit classical apoptotic features, while cells pre-treated with Acanthopanax senticosus prior to EtOH exposure showed decreased occurrence of apoptotic features. In addition, Acanthopanax senticosus pre-treatment was shown to inhibit EtOH-induced increase in caspase-3 mRNA expression and activity. These results suggest that Acanthopanax senticosus may exert a protective effect against EtOH-induced apoptosis of human neuroblastoma cells.

Acupuncture suppresses ischemia-induced increase in c-Fos expression and apoptosis in the hippocampal CA1 region in gerbils.

Acupuncture has been used for the enhancement of functional recovery from various disorders including stroke. In the present study, the effects of acupuncture on the c-Fos expression and apoptosis in the hippocampal CA1 region of gerbils following transient global ischemia were investigated via immunohistochemistry for c-Fos and caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Enhanced Fos, TUNEL, and caspase-3 positivities were detected in the hippocampal CA1 region in the ischemic gerbils. Acupunctural treatment suppressed the ischemia-induced increment in the number of Fos-, TUNEL-, and caspase-3-positive cells: the most potent suppressive effect was observed at the Zusanli acupoint. These results suggest that acupunctural treatment alleviates ischemia-induced apoptosis and may aid in the recovery following ischemic cerebral injury.

Acupuncture increases nitric oxide synthase expression in hippocampus of streptozotocin-induced diabetic rats.

In the present study, the effect of acupuncture at Zusanli acupoint on nitric oxide synthase (NOS) expression in the hippocampus of streptozotocin (STZ)-induced diabetic rats was investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Animals were divided into four groups: the control group, the nondiabetic and acupunctured group, the STZ-induced diabetes group, and the STZ-induced diabetes and acupunctured group. From the results, NADPH-d-positive neurons in the hippocampus were decreased in STZ-induced diabetic rats, while acupuncture increased NOS expression significantly under diabetic conditions. In the present study, it can be suggested that acupuncture treatment may modulate NOS activity in the hippocampus under diabetic conditions.

Treadmill exercise suppresses diabetes-induced increment of neuropeptide Y expression in the hypothalamus of rats.

Diabetes mellitus is a metabolic disorder with serious sequelae in humans. Hyperphagia is a characteristic symptom of diabetes and is a central nervous system-mediated disorder. Neuropeptide Y (NPY) is a 36-amino-acid peptide and is concentrated in the hypothalamus which is an appetite-regulating area. NPY is known to stimulate appetite and decrease energy expenditure. In the present study, the effect of treadmill exercise on the hypothalamic NPY expression in rats with streptozotocin (STZ)-induced diabetes was investigated via immunohistochemistry. Enhanced NPY expression in the paraventricular nucleus and arcuate nucleus was observed in the STZ-induced diabetic rats. Treadmill exercise suppressed a diabetes-induced increase of NPY expression. The present results suggest the possibility that treadmill exercise inhibits diabetes-induced increment of the desire for food.

Protective effect of methanol extract of Uncaria rhynchophylla against excitotoxicity induced by N-methyl-D-aspartate in rat hippocampus.

Uncaria rhynchophylla is a medicinal herb used for convulsive disorders in Oriental medicine. In this study, the effect of the methanol extract of Uncaria rhynchophylla against N-methyl-D-aspartate (NMDA)-induced excitotoxicity was investigated. Pretreatment with the extract of Uncaria rhynchopylla reduced the degree of neuronal damage induced by NMDA exposure in cultured hippocampal slices. In the patch clamp study, Uncaria rhynchophylla significantly inhibited NMDA receptor-activated ion current in acutely dissociated hippocampal CA1 neurons. These results indicate that Uncaria rhynchophylla offers protection against NMDA-induced neuronal injury and inhibitory action on NMDA receptor-mediated ion current may be a mechanism behind the neuroprotective effect of Uncaria rhynchophylla.