Stabilization of mitochondrial function by chlorogenic acid protects against kainic acid-induced seizures and neuronal cell death in rats.

The current study investigated the effect of chlorogenic acid, a polyphenolic compound found in numerous plant products, on a kainic acid-induced seizure rat model and its potential mechanism. Rats were administered chlorogenic acid (10 and 50 mg/kg) intraperitoneally for 30 min before kainic acid (15 mg/kg) intraperitoneal administration. Pretreatment with chlorogenic acid decreased the seizure score, increased the latency to onset of the first seizure, and decreased the mortality rate. Chlorogenic acid pretreatment also resulted in a significant reduction in glutamate elevation and neuronal death in the hippocampus of kainic acid-treated rats. In addition, electron microscopy revealed that kainic acid-induced changes in hippocampal mitochondrial structure were prevented by chlorogenic acid pretreatment. Additionally, the levels of mitochondrial function-related proteins, including sirtuin 3, Complex I, glutamate dehydrogenase 1 and ATP synthase, were increased, and the level of the mitochondrial damage marker cytochrome C was decreased in the hippocampus of chlorogenic acid/kainic acid rats. Furthermore, the expression of mitochondrial biogenesis-related proteins [AMP-activated protein kinase (AMPK), sirtuin1, and peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α)] and mitophagy-related proteins [phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), Parkin, and microtubule-associated protein 1 light chain 3 (LC3)] was decreased in the hippocampus of kainic acid-treated rats, which was reversed by chlorogenic acid pretreatment. These observations reveal the marked neuroprotective potential of chlorogenic acid against kainic acid-induced neurotoxicity and seizures through prevention of glutamate increase and preservation of AMPK/sirtuin 1/PGC-1α-mediated mitochondrial biogenesis and PINK1/Parkin-induced mitophagy to maintain adequate mitochondrial homeostasis and function.

Liu Jun Zi Tang-A Potential, Multi-Herbal Complementary Therapy for Chemotherapy-Induced Neurotoxicity.

Liu Jun Zi Tang (LJZT) has been used to treat functional dyspepsia and depression, suggesting its effects on gastrointestinal and neurological functions. LJZT is currently used as a complementary therapy to attenuate cisplatin-induced side effects, such as dyspepsia. However, its effect on chemotherapy-induced neuropathic pain or neurotoxicity has rarely been studied. Thus, we explored potential mechanisms underlying LJZT protection against cisplatin-induced neurotoxicity. We observed that LJZT attenuated cisplatin-induced thermal hyperalgesia in mice and apoptosis in human neuroblastoma SH-SY5Y cells. Furthermore, it also attenuated cisplatin-induced cytosolic and mitochondrial free radical formation, reversed the cisplatin-induced decrease in mitochondrial membrane potential, and increased the release of mitochondrial pro-apoptotic factors. LJZT not only activated the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter region, but also attenuated the cisplatin-induced reduction of PGC-1α expression. Silencing of the PGC-1α gene counteracted the protection of LJZT. Taken together, LJZT mediated, through anti-oxidative effect and mitochondrial function regulation, to prevent cisplatin-induced neurotoxicity.

Gastrodia elata alleviates mutant huntingtin aggregation through mitochondrial function and biogenesis mediation.

BACKGROUND: According to the Compendium of Materia Medica, Gastrodia elata (GE) Blume is a top-grade herbal medicine frequently used to treat dizziness, headaches, tetanus, and epilepsy, suggesting that it affects neurological functions. Although studies have supported its effects in preventing diverse neurodegenerations such as Huntington's disease (HD), its mechanisms require further investigation. PURPOSE: To investigate the ability of the molecular mechanism of GE to prevent mutant huntingtin (mHTT) protein aggregation by focusing on mitochondrial function and biogenesis, which have been proposed as the therapeutic targets of HD. STUDY DESIGN/METHODS: mHtt overexpression in pheochromocytoma (PC12) cells was used as an in vitro cell model of HD. A retardation assay was applied to measure protein aggregation during Htt expression. Cotransfection with transcriptional genes was used to test their relationships with HTT aggregates by monitoring with a confocal laser scanning microscope. Western blot analysis was used to estimate protein expression under different drug treatments or when cotransfected with other related genes. RESULTS: Mutant, abnormal Htt overexpression resulted in significant protein aggregation in PC12 cells. GE dose-dependently attenuated mHTT aggregates and increased cyclic-AMP response element-binding protein (CREB) phosphorylation. Adenosine A2A-R receptor (A2A-R) antagonist counteracted these phenomena. CREB overexpression significantly attenuated mHTT aggregation. GE increased the promoter activity and expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Furthermore, wild-type PGC-1α but not mutant PGC-1α overexpression attenuated mHTT aggregates. CONCLUSION: GE attenuated mHtt aggregation by mediating mitochondrial function and biogenesis through the A2A-R/PKA/CREB/PGC-1α-dependent pathway.

The relationship between theory of mind and the executive functions: Evidence from patients with frontal lobe damage.

"Theory of mind" (ToM) refers to the ability to predict others' thoughts, intentions, beliefs, and feelings. Evidence from neuropsychology and functional imaging indicates that ToM is a domain-specific or modular architecture; however, research in development psychology has suggested that ToM is the full development of the executive functions in individuals. Therefore, the relationship between ToM and the executive functions needs to be clarified. Since the frontal lobe plays a critical role in the abilities of ToM and the executive functions, patients with frontal lobe damage were recruited for the present study. Assessments of ToM and the executive functions were performed on 23 patients with frontal lobe damage and 20 healthy controls. When controlling for the executive functions, significant differences between the patient and normal groups were found in the affective component of ToM, but not in the cognitive component. The present study suggests that in various social situations, executing ToM abilities requires logical reasoning processes provided by the executive functions. However, the reasoning processes of affective ToM are independent of executive functions.

Effects of repetitive hyperbaric oxygen treatment in patients with acute cerebral infarction: a pilot study.

The role of hyperbaric oxygen therapy (HBOT) in the treatment of acute ischemic stroke is controversial. This prospective study assessed the efficacy and safety of HBOT as adjuvant treatment on 46 acute ischemic stroke in patients who did not receive thrombolytic therapy. The HBOT group (n = 16) received conventional medical treatment with 10 sessions of adjunctive HBOT within 3-5 days after stroke onset, while the control group (n = 30) received the same treatment but without HBOT. Early (around two weeks after onset) and late (one month after onset) outcomes (National Institutes of Health Stroke Scale, NIHSS scores) and efficacy (changes of NIHSS scores) of HBOT were evaluated. The baseline clinical characteristics were similar in both groups. Both early and late outcomes of the HBOT group showed significant difference (P ≤ 0.001). In the control group, there was only significant difference in early outcome (P = 0.004). For early efficacy, there was no difference when comparing changes of NIHSS scores between the two groups (P = 0.140) but there was statistically significant difference when comparing changes of NIHSS scores at one month (P ≤ 0.001). The HBOT used in this study may be effective for patients with acute ischemic stroke and is a safe and harmless adjunctive treatment.

Gastrodia elata prevents huntingtin aggregations through activation of the adenosine A2A receptor and ubiquitin proteasome system.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodia elata Blume (Fam. Orchidaceae) is a traditional Chinese herbal medicine for treating headaches, dizziness, tetanus, epilepsy, and numbness of the limbs, which suggests that it has neuroprotective effect. AIM OF THE STUDY: To validate the neuroprotection of Gastrodia elata in preventing neurodegenerations, such as Huntington's disease (HD). MATERIALS AND METHODS: MTT assay was used to validate the protection of Gastrodia elata. In pheochromocytoma (PC12) cell. Transient transfection of mutant huntingtin (Htt) in PC12 cell was used as an in vitro model of HD. Filter retardation assay was used to measure Htt-induced protein aggregations. Proteasome activity was monitored by transfection of pZsProSensor-1 and imaged by a confocal laser scanning microscope. RESULTS: This protection of Gastrodia elata could be blocked by an A(2A)-R antagonist and a protein kinase A (PKA) inhibitor, indicating an A(2A)-R signaling event. Gastrodia elata could reverse mutant Htt-induced protein aggregations and proteasome de-activation through A(2A)-R signaling. In addition, activation of PKA tended to activate proteasome activity and reduce mutant Htt protein aggregations. The proteasome inhibitor, MG 132, blocked Gastrodia elata-mediated suppression of mutant Htt aggregations. CONCLUSION: Gastrodia elata prevented mutant Htt aggregations and increased proteasomal activity by targeting the A(2A)-R through PKA-dependent pathway.

Polymorphism distribution of prion protein codon 117, 129 and 171 in Taiwan.

Prion diseases compass transmissible spongiform neurodegenerative diseases from various causes, including the genetic and infectious ones. We investigated the prevalence of codon 117, 129 and 171 polymorphism in prion protein (PrP) in Taiwanese, mainly for the sake of the informative absence of this genetic distribution. Our subjects were 419 aged ones of Han ethic origin. We evaluated the PrP gene (PRNP) polymorphism by restriction fragment length polymorphism, after amplification of their genomic DNAs by polymerase chain reactions with specific primers, digested by restriction enzyme PvuII (for codon 117), NspI (for codon 129), and BbvI (for codon 171), respectively, and confirmed by nucleotide sequencing. All of the subjects were homozygotes at codon 117 (Ala/Ala, gca/gca) and 171 (Asn/Asn, aac/aac). There were no valine homozygotes (Val/Val) in our 419 subjects, and nine subjects (2.1%) showed methionine-valine heterozygosity (Mal/Val, atg/gtg). The methionine homozygotes (Met/Met) comprised the major population (97.9%), and the prevalence of distribution is different to that seen in Caucasians. The almost 100% conservation of the domain from codon 117 to 171 implies the warranty of PrP in cellular functions. The high prevalence of Met/Met alleles in Taiwan did not imply an increased risk of CJD, and the genetic susceptibility of CJD by codon 129 of PrP may be still elusive for the infectivity.