Neuroprotective potential of the Amazonian fruits Euterpe oleracea Mart. and Paullinia cupana Kunth

Abstract Acai (Euterpe oleracea Mart.) and guarana (Paullinia cupana Kunth) are native species from the Amazon Forest that in folk medicine are used to treat several diseases due to their anti-inflammatory and antioxidant properties. This review brings together findings from different studies on the potential neuroprotective effects of acai and guarana, highlighting the importance of the conservation and sustainable exploitation of the Amazon Forest. A bibliographic survey in the PubMed database retrieved indexed articles written in English that focused on the effects of acai and guarana in in vitro and in vivo models of neurodegenerative diseases. In general, treatment with either acai or guarana decreased neuroinflammation, increased antioxidant responses, ameliorated depression, and protected cells from neurotoxicity mediated by aggregated proteins. The results from these studies suggest that flavonoids, anthocyanins, and carotenoids found in both acai and guarana have therapeutic potential not only for neurodegenerative diseases, but also for depressive disorders. In addition, acai and guarana show beneficial effects in slowing down the physiological aging process. However, toxicity and efficacy studies are still needed to guide the formulation of herbal medicines from acai and guarana.

Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities.

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by the progressive degeneration of neurons. Although the etiology and pathogenesis of neurodegenerative diseases have been studied intensively, the mechanism is still in its infancy. In general, most neurodegenerative diseases share common molecular mechanisms, and multiple risks interact and promote the pathologic process of neurogenerative diseases. At present, most of the approved drugs only alleviate the clinical symptoms but fail to cure neurodegenerative diseases. Numerous studies indicate that dietary plant polyphenols are safe and exhibit potent neuroprotective effects in various neurodegenerative diseases. However, low bioavailability is the biggest obstacle for polyphenol that largely limits its adoption from evidence into clinical practice. In this review, we summarized the widely recognized mechanisms associated with neurodegenerative diseases, such as misfolded proteins, mitochondrial dysfunction, oxidative damage, and neuroinflammatory responses. In addition, we summarized the research advances about the neuroprotective effect of the most widely reported dietary plant polyphenols. Moreover, we discussed the current clinical study and application of polyphenols and the factors that result in low bioavailability, such as poor stability and low permeability across the blood-brain barrier (BBB). In the future, the improvement of absorption and stability, modification of structure and formulation, and the combination therapy will provide more opportunities from the laboratory into the clinic for polyphenols. Lastly, we hope that the present review will encourage further researches on natural dietary polyphenols in the treatment of neurodegenerative diseases.

ConjuPepDB: a database of peptide-drug conjugates.

Peptide-drug conjugates are organic molecules composed of (i) a small drug molecule, (ii) a peptide and (iii) a linker. The drug molecule is mandatory for the biological action, however, its efficacy can be enhanced by targeted delivery, which often also reduces unwanted side effects. For site-specificity the peptide part is mainly responsible. The linker attaches chemically the drug to the peptide, but it could also be biodegradable which ensures controlled liberation of the small drug. Despite the importance of the field, there is no public comprehensive database on these species. Herein we describe ConjuPepBD, a freely available, fully annotated and manually curated database of peptide drug conjugates. ConjuPepDB contains basic information about the entries, e.g. CAS number. Furthermore, it also implies their biomedical application and the type of chemical conjugation employed. It covers more than 1600 conjugates from ∼230 publications. The web-interface is user-friendly, intuitive, and useable on several devices, e.g. phones, tablets, PCs. The webpage allows the user to search for content using numerous criteria, chemical structure and a help page is also provided. Besides giving quick insight for newcomers, ConjuPepDB is hoped to be also helpful for researchers from various related fields. The database is accessible at: https://conjupepdb.ttk.hu/.

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant.

Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound-Δ9-tetrahydrocannabinol (Δ9-THC)-as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS). Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa. However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself. In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.

The neurosteroids, allopregnanolone and progesterone, induce autophagy in cultured astrocytes.

Recent studies have suggested that neurosteroids such as pregnenolone, progesterone (PG) and their derivatives, have a role in activating autophagy in addition to diverse other functions. In our previous studies, we demonstrated that cellular free Zn(2+) is involved in oxidative stress-induced autophagy and autophagic cell death in astrocytes. In the present study, we examined the possibility that neurosteroids, allopregnanolone (Allo) and PG, also activate autophagy in cultured mouse astrocytes through modulation of intracellular Zn(2+). Exposure of astrocytes to 250 nM Allo or 500 nM PG caused cytosolic vacuoles to appear within a few hours of treatment onset. Live-cell confocal microscopy of astrocytes transfected with red fluorescent protein-conjugated LC3 (RFP-LC3), a marker for autophagic vacuoles (AVs), as well as transmission electron microscopy, revealed that these vacuoles were AVs. In addition, Western blots showed increases in LC3-II levels. Interestingly, mTOR and Akt were concurrently activated, and their blockade further increased LC3-II levels and caused some cell death. These results indicate that co-activation of mTOR and Akt may act to limit neurosteroid-induced autophagy and thus inhibit autophagic cell death. As in other cases of autophagy, cellular Zn(2+) levels increased after treatment with neurosteroids. The neurosteroid-induced increase in LC3-II levels was inhibited by addition of the Zn(2+) chelator TPEN. Both the increase in LC3-II levels and activation of Akt and mTOR by neurosteroids were all mediated by PG receptors, as the effects were blocked by the addition of RU-486, a PG receptor antagonist. Moreover, mutant huntingtin (mHtt) aggregates in GFP-mHttQ74-transfected astrocytes were substantially reduced by neurosteroid treatment, indicating that neurosteroid-induced autophagy may be functional. Present results demonstrate that Allo and PG activate autophagy in astrocytes. Notably, unlike several other autophagy inducers that, in excess, may cause autophagic cell death, Allo and PG are relatively non-toxic, possibly because of concurrent Akt and mTOR activation. Thus, as natural endogenous brain substances, Allo and PG may have a potential as therapeutic agents in neurodegenerative conditions in which abnormal protein aggregates are involved.

Protective effects of organoselenium compounds against methylmercury-induced oxidative stress in mouse brain mitochondrial-enriched fractions

We evaluated the potential neuroprotective effect of 1-100 µM of four organoselenium compounds: diphenyl diselenide, 3’3-ditri-fluoromethyldiphenyl diselenide, p-methoxy-diphenyl diselenide, and p-chloro-diphenyl diselenide, against methylmercury-induced mitochondrial dysfunction and oxidative stress in mitochondrial-enriched fractions from adult Swiss mouse brain. Methylmercury (10-100 µM) significantly decreased mitochondrial activity, assessed by MTT reduction assay, in a dose-dependent manner, which occurred in parallel with increased glutathione oxidation, hydroperoxide formation (xylenol orange assay) and lipid peroxidation end-products (thiobarbituric acid reactive substances, TBARS). The co-incubation with diphenyl diselenide (100 µM) completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels caused by methylmercury. The compound 3’3-ditrifluoromethyldiphenyl diselenide provided a partial but significant protection against methylmercury-induced mitochondrial dysfunction (45.4 ± 5.8 percent inhibition of the methylmercury effect). Diphenyl diselenide showed a higher thiol peroxidase activity compared to the other three compounds. Catalase blocked methylmercury-induced TBARS, pointing to hydrogen peroxide as a vector during methylmercury toxicity in this model. This result also suggests that thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress. Our results show that diphenyl diselenide and potentially other organoselenium compounds may represent important molecules in the search for an improved therapy against the deleterious effects of methylmercury as well as other mercury compounds.

ß-dicarbonyl enolates: a new class of neuroprotectants.

Curcumin, phloretin and structurally related phytopolyphenols have well-described neuroprotective properties that appear to be at least partially mediated by 1,3-dicarbonyl enol substructures that form nucleophilic enolates. Based on their structural similarities, we tested the hypothesis that enolates of simple 1,3-dicarbonyl compounds such as acetylacetone might also possess neuroprotective actions. Our results show that the ß-diketones, particularly 2-acetylcyclopentanone, protected rat striatal synaptosomes and a neuronal cell line from thiol loss and toxicity induced by acrolein, an electrophilic α,ß-unsaturated aldehyde. The 1,3-dicarbonyl compounds also provided substantial cytoprotection against toxicity induced by hydrogen peroxide in a cellular model of oxidative stress. Initial chemical characterization in cell-free systems indicated that the 1,3-dicarbonyl compounds acted as surrogate nucleophilic targets that slowed the rate of sulfhydryl loss caused by acrolein. Although the selected 1,3-dicarbonyl congeners did not scavenge free radicals, metal ion chelation was a significant property of both acetylacetone and 2-acetylcyclopentanone. Our data suggest that the 1,3-dicarbonyl enols represent a new class of neuroprotectants that scavenge electrophilic metal ions and unsaturated aldehydes through their nucleophilic enolate forms. As such, these enols might be rational candidates for treatment of acute or chronic neurodegenerative conditions that have oxidative stress as a common molecular etiology.

Characterization of neurotoxic effects of NMDA and the novel neuroprotection by phytopolyphenols in mice.

Excitotoxicity plays a major role in various neurological disorders. In this study, we explored the behavioral and neurotoxic effects of intraventricular NMDA administration in mice. After NMDA injection, acute seizures were followed by impairments in locomotor activity, motor performance on a rotarod, and climbing ability. Mice killed 1 day after NMDA administration showed increased synaptosomal reactive oxygen species ROS production and calcium concentration and decreased mitochondrial membrane potential, mitochondrial reductase activities, and neuronal membrane Na+, K+ -ATPase and mg2+ -ATPase activities. One and 3 days after excitotoxic injury, Golgi stains showed that dendritic length and spine density were significantly decreased in neurons of the hippocampal dentate gyrus. Some mice received honokiol, tea polyphenol plus memantine, and honokiol plus memantine prior to NMDA treatment; the occurrence of generalized seizures was attenuated, seizure scores were reduced, latency to generalized seizures was prolonged, and motor impairments were lessened. Moreover, all of the neurochemical changes of the synaptosomes were also ameliorated. In conclusion, the behavioral and neurotoxic effects of intracerebroventricular injection of NMDA were ameliorated by treatment with honokiol alone or combined treatment with either tea polyphenol plus memantine or honokiol plus memantine, but only partly by either tea polyphenol or memantine alone. The therapeutic potential of these neuroprotective regimens in treating excitotoxicity-related diseases merits for further investigation.

In vitro antioxidant activities and an investigation of neuroprotection by six Salvia species from Iran: a comparative study.

Methanolic extracts of six species of Salvia (S. hydrangea, S. lachnocalyx, S. macilenta, S. multicalis, S. sclarea and S. xanthocheila) were analyzed for their antioxidant properties, ability to prevent DNA damage by free radicals, and neuroprotective effects. Several biochemical assays were used to evaluate their antioxidant properties: DPPH(), FRAP, beta-carotene bleaching and TEAC assays. The amounts of phenolics and flavonoids were also determined. Comparison study of Salvia species showed that extracts from S. hydrangea and S. macilenta are strong antioxidants and that from S. lachnocalyx is a weak one. Furthermore, extracts from all of these species can at high concentrations (50mug/ml) inhibit DNA damage by free radicals. Furthermore, these species not only showed no cytotoxic effects in nerve growth factor (NGF)-differentiated PC12 cells, they also protected them against H(2)O(2)-induced cell death. Thus these plants may be candidates for treating neurodegenerative diseases.

[Nootropes (cognition enhancers) and neuroprotectors].

The paper reviews the existing and future nootropic drugs (cognition enhancers) with different mechanisms of action and heterogenous chemical structures, which have been developed on the basis of knowledge of the mechanisms of learning, memory and forgetting, as well as degenerative processes in aging brain and disease-associated cognitive impairments. These agents influence on acetylcholine-, glutamate-, GABA-, 5-HT-, dopamine-, histamine-, adenosine-, phosphodiesterase-, neurotrophic- systems, and neurohormones. Neuropeptides and their analogs, blood flow enhancers, calcium-channel blockers, antioxidants and vitamins and herbal preparations, and some other agents improving cerebral metabolism and influencing the neurodegeneracy involved in Alzheimer's disease are considered. An original classification of cognition enhancers, based on mechanisms of their action, includes more than 200 drugs in current use and those currently under development.