1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ) has previously been found to have effective anti-oxidant and anti-lipid-peroxidative activity. We aimed to elucidate whether HTHQ can prevent dopaminergic neuronal cell death by investigating the effect on l-DOPA-induced cytotoxicity in PC12 cells. HTHQ protected from both l-DOPA-induced cell death and superoxide dismutase activity reduction. When assessing the effect of HTHQ on oxidative stress-related signaling pathways, HTHQ inhibited l-DOPA-induced phosphorylation of sustained extracellular signal-regulated kinases (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1/2). HTHQ also normalized l-DOPA-reduced Bcl-2-associated death protein (Bad) phosphorylation and Bcl-2-associated X protein (Bax) expression, promoting cell survival. Taken together, HTHQ exhibits protective effects against l-DOPA-induced cell death through modulation of the ERK1/2-p38MAPK-JNK1/2-Bad-Bax signaling pathway in PC12 cells. These results suggest that HTHQ may show ameliorative effects against oxidative stress-induced dopaminergic neuronal cell death, although further studies in animal models of Parkinson’s disease are required to confirm this. Full article

A series of fourteen new asymmetrical 1,3-diketone derivatives have been synthesized and evaluated in the ABTS, FRAP and DPPH assays as a new chemotype with antioxidant and drug-like properties. All the compounds displayed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y cell line. Among them, (3Z,5E)-6-(2,5-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one (6b) and (3Z,5E)-6-(2,3-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one (7b) with excellent solubility and chemical stability in biorelevant media, have also shown a similar Fe⁺² chelation behavior to that of curcumin. Additionally, both derivatives 6b and 7b have afforded good neuroprotection activity against H₂O₂ induced oxidative stress in the same neuronal cell line, with a significant reduction of intracellular ROS levels, in parallel with a good recovery of the Mitochondrial Membrane Potential (ΔΨ_m). Compounds 6b and 7b with a promising antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitute a new interesting chemical class with high potential as new therapeutic agents against neurodegenerative diseases. Full article

Glucosylation of the 21-hydroxyl group of glucocorticoid changes its solubility into hydrophilicity from hydrophobicity and, as with glucocorticoid glucuronides as a moving object in vivo, it is conceivable that it exhibits the same behavior. Therefore, glucosylation to the 21-hydroxyl group while maintaining the 11β-hydroxyl group is particularly important, and glucosylation of corticosterone was confirmed by high-resolution mass spectrometry and 1D (¹H and ¹³C) and 2D (COSY, ROESY, HSQC-DEPT and HMBC) NMR. Moreover, the difference in bioactivity between corticosterone and corticosterone 21-glucoside was investigated in vitro. Corticosterone 21-glucoside showed greater neuroprotective effects against H₂O₂-induced cell death and reactive oxygen species (ROS) compared with corticosterone. These results for the first time demonstrate that bioconversion of corticosterone through the region-selective glucosylation of a novel compound can present structural potential for developing new neuroprotective agents. Full article

Abstract: Memory extinction is referred to as a learning process in which a conditioned response (CR) progressively reduces over time as an animal learns to uncouple a response from a stimulus. Extinction occurs when the rat is placed into a context without shock after training. Docosahexaenoic acid (DHA, C22:6, n-3) is implicated in memory formation in mammalian brains. In a two-way active shuttle-avoidance apparatus, we examined whether DHA affects the extinction memory and the expression of brain cognition-related proteins, including gastrin-releasing peptide receptor (GRPR), brain-derived neurotrophic factor receptor (BDNFR) tyrosine kinase receptor B (TrKB), and N-methyl-d-aspartate receptor (NMDAR) subunits NR2A and NR2B. Also, the protein levels of GRP, BDNF, postsynaptic density protein-95 (PSD-95), and vesicular acetylcholine transporter (VAChT), and the antioxidative potentials, in terms of lipid peroxide (LPO) and reactive oxygen species (ROS), were examined in the hippocampus. During the acquisition phase, the rats received a conditioned stimulus (CS-tone) paired with an unconditioned stimulus (UCS foot shock) for three consecutive days (Sessions S1, S2, and S3, each consisting of 30-trials) after 12 weeks of oral administration of DHA. After a three-day interval, the rats were re-subjected to two extinction sessions (S4, S5), each comprising 30 trials of CS alone. During the acquisition training in S1, the shock-related avoidance frequency (acquisition memory) was significantly higher in the DHA-administered rats compared with the control rats. The avoidance frequency, however, decreased with successive acquisition trainings in sessions S2 and S3. When the rats were subjected to the extinction sessions after a break for consolidation, the conditioned response (CR) was also significantly higher in the DHA-administered rats. Interestingly, the freezing responses (frequency and time) also significantly decreased in the DHA-administered rats, thus suggesting that a higher coping capacity was present during fear stress in the DHA-administered rats. DHA treatments increased the mRNA levels of GRPR, BDNF receptor TrKB, and NMDAR subunit NR2B. DHA also increased the protein levels of GRP, BDNF, PSD-95, and VAChT, and the antioxidative potentials in the hippocampus. These results suggest the usefulness of DHA for treating stress disorders. Full article

Suramin is a trypan blue analogon originally developed to treat protozoan infections, which was found to have diverse antitumor effects. One of the most severe side effects in clinical trials was the development of a peripheral sensory-motor polyneuropathy. In this study, we aimed to investigate suramin-induced neuropathy with a focus on calcium (Ca²⁺) homeostasis as a potential pathomechanism. Adult C57Bl/6 mice treated with a single injection of 250 mg/kg bodyweight suramin developed locomotor and sensory deficits, which were confirmed by electrophysiological measurements showing a predominantly sensory axonal-demyelinating polyneuropathy. In a next step, we used cultured dorsal root ganglia neurons (DRGN) as an in vitro cell model to further investigate underlying pathomechanisms. Cell viability of DRGN was significantly decreased after 24-hour suramin treatment with a calculated IC₅₀ of 283 µM. We detected a suramin-induced Ca²⁺ influx into DRGN from the extracellular space, which could be reduced with the voltage-gated calcium channel (VGCC) inhibitor nimodipine. Co-incubation of suramin and nimodipine partially improved cell viability of DRGN after suramin exposure. In summary, we describe suramin-induced neurotoxic effects on DRGN as well as potentially neuroprotective agents targeting intracellular Ca²⁺ dyshomeostasis. Full article

In order to utilize the neuroprotective properties of polycyclic cage compounds, and explore the NO-donating ability of nitrophenyl groups, an array of compounds was synthesized where the different nitrophenyl groups were appended on oxa and aza-bridged cage derivatives. Biological evaluations of the compounds were done for cytotoxicity, neuroprotective abilities, the inhibition of N-methyl-d-aspartate (NMDA)-mediated Ca²⁺ influx, the inhibition of voltage-mediated Ca²⁺ influx, and S-nitrosylation abilities. All of the compounds showed low toxicity. With a few exceptions, most of the compounds displayed good neuroprotection and showed inhibitory activity for NMDA-mediated and voltage-gated calcium influx, ranging from high (>70%) to low (20–39%) inhibition. In the S-nitrosylation assay, the compounds with the nitro moiety as the NO-donating group exhibited low to good nitrosylation potency compared to the positive controls. From the biological evaluation of the tested compounds, it was not possible to obtain a simple correlation that could explain the results across all of the biological study domains. This can be ascribed to the independent processes evaluated in the different assays, which reiterate that neuroprotection is a result of multifactorial biochemical mechanisms and interactions. However, these results signify the important aspects of the pentacylcoundecylamine neuroprotectants across different biological study realms. Full article

α-Synuclein is a neuronal protein that is at the center of focus in understanding the etiology of a group of neurodegenerative diseases called α-synucleinopathies, which includes Parkinson’s disease (PD). Despite much research, the exact physiological function of α-synuclein is still unclear. α-Synuclein has similar biophysical properties as apolipoproteins and other lipid-binding proteins and has a high affinity for cholesterol. These properties suggest a possible role for α-synuclein as a lipid acceptor mediating cholesterol efflux (the process of removing cholesterol out of cells). To test this concept, we “loaded” SK-N-SH neuronal cells with fluorescently-labelled cholesterol, applied exogenous α-synuclein, and measured the amount of cholesterol removed from the cells using a classic cholesterol efflux assay. We found that α-synuclein potently stimulated cholesterol efflux. We found that the process was dose and time dependent, and was saturable at 1.0 µg/mL of α-synuclein. It was also dependent on the transporter protein ABCA1 located on the plasma membrane. We reveal for the first time a novel role of α-synuclein that underscores its importance in neuronal cholesterol regulation, and identify novel therapeutic targets for controlling cellular cholesterol levels. Full article

Senescent astrocytes in aging brain express senescence-associated secretory phenotype (SASP) and link with increased brain aging and its related diseases. In order to determine whether ginsenosides ameliorate the astrocytic senescence in vitro, human astrocytic CRT cells and primary rat astrocytes were used in the present study. Ginsenosides Rg1, Re, Rb1 and Rg3 (5 μg/mL) could effectively prevent the astrocytic senescence induced by H₂O₂ exposure. However, these ginsenosides did not reverse the astrocytic senescence. Importantly, senescent astrocytes herein produce SASP. The expression of major components of SASP, IL-6 and IL-8, are greatly increased in senescent astrocytes. Ginsenoside Rg3 (10 μg/mL) effectively suppressed the expressions of IL-6 and IL-8, which is associated with regulations of NF-κB and p38MAPK activation. In addition, after incubation with Rg3, conditioned medium from senescent astrocytic CRT cells significantly decreased the ability to promote the proliferation of astrocytoma U373-MG, U87-MG and U251-MG cells compared with non-treated senescent samples. Similar patterns were confirmed in chemotherapy-induced glioblastoma senescent cells. The present study explored a potential candidate for amelioration of astrocytic senescence and SASP in brain aging, which provided a basis for developing strategies to reduce the dark side of senescence in normal or pathological aging process. Full article

Fibrillar accumulation of A53T mutant α-synuclein (A53T-AS) in Lewy bodies is a symptom of Parkinsonism. Inhibitions of the overexpression and fibrillar aggregation of α-synuclein (AS) in vivo could be a promising strategy for treating Parkinson’s disease (PD). In this study, at concentrations lower than 1 mM, trehalose decreased the A53T-AS expression level in transduced PC12 cells. Although H₂O₂ and aluminum ions increased the expression level and neurotoxicity of A53T-AS in cells, proper trehalose concentrations inhibited the event. These studies adequately prove that trehalose at an appropriate dose would be potentially useful for PD treatment. Full article

In our study, we attempted to investigate the influences of P-glycoprotein (P-gp) on DL0410, a novel synthetic molecule for Alzheimer’s disease (AD) treatment, for intestinal absorption and blood-brain barrier permeability in vitro and related binding mechanisms in silico. Caco-2, MDCK, and MDCK-MDR1 cells were utilized for transport studies, and homology modelling of human P-gp was built for further docking study to uncover the binding mode of DL0410. The results showed that the apparent permeability (Papp) value of DL0410 was approximately 1 × 10⁻⁶ cm/s, indicating the low permeability of DL0410. With the presence of verapamil, the directional transport of DL0410 disappeared in Caco-2 and MDCK-MDR1 cells, suggesting that DL0410 should be a substrate of P-gp, which was also confirmed by P-gp ATPase assay. In addition, DL0410 could competitively inhibit the transport of Rho123, a P-gp known substrate. According to molecular docking, we also found that DL0410 could bind to the drug binding pocket (DBP), but not the nucleotide binding domain (NBD). In conclusion, DL0410 was a substrate as well as a competitive inhibitor of P-gp, and P-gp had a remarkable impact on the intestine and brain permeability of DL0410, which is of significance for drug research and development. Full article

Irisin, a skeletal muscle-secreted myokine, produced in response to physical exercise, has protective functions in both the central and the peripheral nervous systems, including the regulation of brain-derived neurotrophic factors. In particular, irisin is capable of protecting hippocampus. Since this area is the region of the brain that is most susceptible to Alzheimer’s disease (AD), such beneficial effect may inhibit or delay the emergence of neurodegenerative diseases, including AD. Also, the factors engaged in irisin formation appear to suppress Aβ aggregation, which is the pathological hallmark of AD. This review is based on the hypothesis that irisin produced by physical exercise helps to control AD progression. Herein, we describe the physiology of irisin and its potential role in delaying or preventing AD progression in human. Full article

Oridonin, a diterpenoid natural product commonly used in East Asian herbal medicine, is garnering increased attention in the biomedical community due to its extensive biological activities that include antitumor, anti-inflammatory, antimicrobial, hepatic fibrosis prevention, and neurological effects. Over the past decade, significant progress has been made in structure activity relationship and mechanism of action studies of oridonin for the treatment of cancer and other diseases. This review provides a brief summary on oridonin and its analogs in cancer drug discovery and antiinflammation and highlights its emerging therapeutic potential in neuroprotection applications. Full article

Traditional Chinese medicine has been practiced for centuries in East Asia. Herbs are used to maintain health and cure disease. Certain Chinese herbs are known to protect and improve the brain, memory, and nervous system. To apply ancient knowledge to modern science, some major natural therapeutic compounds in herbs were extracted and evaluated in recent decades. Emerging studies have shown that herbal compounds have neuroprotective effects or can ameliorate neurodegenerative diseases. To understand the mechanisms of herbal compounds that protect against neurodegenerative diseases, we summarize studies that discovered neuroprotection by herbal compounds and compound-related mechanisms in neurodegenerative disease models. Those compounds discussed herein show neuroprotection through different mechanisms, such as cytokine regulation, autophagy, endoplasmic reticulum (ER) stress, glucose metabolism, and synaptic function. The interleukin (IL)-1β and tumor necrosis factor (TNF)-α signaling pathways are inhibited by some compounds, thus attenuating the inflammatory response and protecting neurons from cell death. As to autophagy regulation, herbal compounds show opposite regulatory effects in different neurodegenerative models. Herbal compounds that inhibit ER stress prevent neuronal death in neurodegenerative diseases. Moreover, there are compounds that protect against neuronal death by affecting glucose metabolism and synaptic function. Since the progression of neurodegenerative diseases is complicated, and compound-related mechanisms for neuroprotection differ, therapeutic strategies may need to involve multiple compounds and consider the type and stage of neurodegenerative diseases. Full article

Traumatic brain injury (TBI) is one of the most frequent causes of combat casualties in Operations Iraqi Freedom (OIF), Enduring Freedom (OEF), and New Dawn (OND). Although less common than combat-related blast exposure, there have been significant numbers of blast injuries in civilian populations in the United States. Current United States Department of Defense (DoD) ICD-9 derived diagnoses of TBI in the DoD Health Care System show that, for 2016, severe and moderate TBIs accounted for just 0.7% and 12.9%, respectively, of the total of 13,634 brain injuries, while mild TBIs (mTBIs) accounted for 86% of the total. Although there is a report that there are differences in the frequency of long-term complications in mTBI between blast and non-blast TBIs, clinical presentation is classified by severity score rather than mechanism because severity scoring is associated with prognosis in clinical practice. Blast TBI (bTBI) is unique in its pathology and mechanism, but there is no treatment specific for bTBIs—these patients are treated similarly to TBIs in general and therapy is tailored on an individual basis. Currently there is no neuroprotective drug recommended by the clinical guidelines based on evidence. Full article

In this review, the potential causes of ageing are discussed. We seek to gain insight into the main physiological functions of mitochondria and discuss alterations in their function and the genome, which are supposed to be the central mechanisms in senescence. We conclude by presenting the potential modulating role of the kynurenine pathway in the ageing processes. Mitochondrial dynamics are supposed to have important physiological roles in maintaining cell homeostasis. During ageing, a decrease in mitochondrial dynamics was reported, potentially compromising the function of mitochondria. Mitochondrial biogenesis not only encompasses mitochondrial dynamics, but also the regulation of transcription and translation of genes, and mitochondria are supposed to play a prominent role in cell death during senescence. Defects in the mtDNA replication machinery and failure in the repair of mtDNA might result in the accumulation of mutations, leading to mitochondrial dysfunction and bioenergetic failure of the cell. The role of reactive oxygen species (ROS) in the ageing processes is widely acknowledged. Exaggerated oxidative damage to mDNA is supposed to take place during senescence, including single-nucleotide base alterations, nucleotide base pair alterations, chain breaks and cross linkage. A broad repertoire for the repair of DNA faults has evolved, but they do not function efficiently during senescence. Poly (ADP-ribose) polymerase (PARP) is an enzyme that assists in DNA repair, i.e., it participates in the repair of single-stranded DNA nicks, initiating base excision repair (BER). In the case of extensive DNA damage, PARP-1 becomes overactivated and rapidly depletes the intracellular NAD⁺ and ATP pools. This results in a profound energy loss of the cell and leads to cell dysfunction, or even cell death. Alterations in the kynurenine system have been linked with ageing processes and several age-related disorders. The kynurenine pathway degrades tryptophan (TRP) to several metabolites, among others kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN). The end product of the route is NAD⁺. The first metabolic reaction is mediated by TRP-2,3-dioxygenase (TDO) or indolamine-2,3-dioxygenases (IDO), the latter being induced by inflammation, and it is thought to have a significant role in several disorders and in ageing. Research is currently focusing on the KYN pathway, since several intermediates possess neuro- and immunoactive properties, and hence are capable of modulating the activity of certain brain cells and inflammatory responses. During ageing, and in many age-associated disorders like obesity, dyslipidaemia, hypertension, insulin resistance and neurodegenerative diseases, low-grade, sustained inflammation and upregulation of IDO have been reported. However, TRP downstream catabolites create a negative feedback loop by weakening the activated immune system through several actions, including a decline in the Th1 response and an enhancement of Th2-type processes. The broad actions of the KYN-intermediates in brain excitation/inhibition and their role in regulating immune responses may provide the possibility of modifying the pathological processes in an array of age-associated diseases in the future. Full article