The Potential of Targeting Autophagy-Related Non-coding RNAs in the Treatment of Alzheimer's and Parkinson's Diseases.

Clearance of accumulated protein aggregates is one of the functions of autophagy. Recently, a clearer understanding of non-coding RNAs (ncRNAs) functions documented that ncRNAs have important roles in several biological processes associated with the development and progression of neurodegenerative disorders. Subtypes of ncRNA, including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), are commonly dysregulated in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Dysregulation of these non-coding RNAs has been associated with inhibition or stimulation of autophagy. Decreased miR-124 led to decreased/increased autophagy in experimental model of Alzheimer and Parkinson diseases. Increased BACE1-AS showed enhanced autophagy in Alzheimer disease by targeting miR-214-3p, Beclin-1, LC3-I/LC3-II, p62, and ATG5. A significant increase in NEAT1led to stimulated autophagy in experimental model of PD by targeting PINK1, LC3-I, LC3-II, p62 and miR-374c-5p. In addition, increased BDNF-AS and SNHG1 decreased autophagy in MPTP-induced PD by targeting miR-125b-5p and miR-221/222, respectively. The upregulation of circNF1-419 and circSAMD4A resulted in an increased autophagy by regulating Dynamin-1 and miR-29c 3p, respectively. A detailed discussion of miRNAs, circRNAs, and lncRNAs in relation to their autophagy-related signaling pathways is presented in this study.

Non-Coding RNAs and Neurodegenerative Diseases: Information of their Roles in Apoptosis.

Apoptosis can be known as a key factor in the pathogenesis of neurodegenerative disorders. In disease conditions, the rate of apoptosis expands and tissue damage may become apparent. Recently, the scientific studies of the non-coding RNAs (ncRNAs) has provided new information of the molecular mechanisms that contribute to neurodegenerative disorders. Numerous reports have documented that ncRNAs have important contributions to several biological processes associated with the increase of neurodegenerative disorders. In addition, microRNAs (miRNAs), circular RNAs (circRNAs), as well as, long ncRNAs (lncRNAs) represent ncRNAs subtypes with the usual dysregulation in neurodegenerative disorders. Dysregulating ncRNAs has been associated with inhibiting or stimulating apoptosis in neurodegenerative disorders. Therefore, this review highlighted several ncRNAs linked to apoptosis in neurodegenerative disorders. CircRNAs, lncRNAs, and miRNAs were also illustrated completely regarding the respective signaling pathways of apoptosis.

Protective effects of nanocurcumin against stress-induced deterioration in the intestine.

The therapeutic activities of curcumin have long been investigated in some chronic and inflammatory diseases. This study was designed to investigate the protective effects of nanocurcumin on intestinal barrier function, apoptosis, and oxidative stress in rats exposed to traffic noise. Forty rats were divided into four groups: two traffic noise-exposed groups of animals that received either vehicle (NOISE) or nanocurcumin (NCUR + NOISE) and two control groups that either remained intact (CON) or received nanocurcumin (NCUR). Nanocurcumin injection (15 mg/Kg/ip) and traffic noise exposure were administered daily for two weeks. The relative protein expression of intestinal tight junctions, occludin, and ZO-1 and Bax/Bcl-2 ratio was measured to evaluate barrier integrity and apoptosis in intestinal samples, respectively. Plasma D-lactate concentration was examined as a criterion of intestinal permeability. Corticosterone, superoxide dismutase (SOD) activity, glutathione (GSH), total antioxidant capacity (TAC), and nitrite were measured in serum. The noise exposure increased Bax/Bcl-2 ratio, corticosterone, and oxidative stress in the NOISE animals. Nanocurcumin treatment improved the Bax/Bcl-2 ratio and reduced corticosterone and oxidative stress in the NCUR + NOISE animals. The expression of tight junction proteins was decreased while the concentration of D-lactate was increased in the NOISE animals. Nanocurcumin did not efficiently impact the expression of tight junction proteins and the D-lactate level in the NCUR + NOISE group. Nanocurcumin administration displayed antioxidant and anti-apoptotic roles in the noise-exposed rats, however, it did not affect the intestinal barrier integrity. We concluded that reduced apoptosis in the intestine might be related to the antioxidant activity of nanocurcumin and its modulatory effects on the HPA axis in the nanocurcumin-treated animals.

Nanocurcumin substantially alleviates noise stress-induced anxiety-like behavior: The roles of tight junctions and NMDA receptors in the hippocampus.

Environmental noise stress affects non-auditory brain regions such as the hippocampus; an area of the brain implicated in cognition and emotion. Recent experimental data indicate that dysfunction of the blood-brain barrier (BBB) and overexpression of NMDA receptors may cause anxiety. In this experiment, we evaluated the effect of nanocurcumin on anxiety-like behavior and the expression of tight junctions and NMDA receptor subunits in the hippocampus of rats exposed to traffic noise. Forty rats were assigned to control (CON), stress (ST), nanocurcumin (NC), and nanocurcumin+stress (NC+ST) groups. Anxiety-like behavior was evaluated through an elevated zero maze apparatus. The gene expression of tight junctions and NMDA receptor subunits was examined by real-time PCR in the hippocampus. Statistical analysis showed that noise exposure developed anxiety-like behavior and elevated the corticosterone level in the ST group compared to the CON group. The nanocurcumin administration decreased the stress and anxiety in the NC+ST group compared to the ST animals. While the noise stress reduced the gene expression of tight junctions occludin, claudin-5, and ZO-1, the nanocurcumin administration increased them in the NC+ST animals. Furthermore, the noise stress elevated the gene expression of the NMDA receptor subunits GRIN1 and GRIN2B. The NC+ST animals showed a modification of these subunits compared to the ST animals. Our findings showed that noise exposure promotes stress and anxiety and impairs the NMDA receptor structure and BBB integrity. The nanocurcumin treatment partly restores the destructive effects of noise exposure.

Good bacteria, oxidative stress and neurological disorders: Possible therapeutical considerations.

Although oxidative agents such as free radicals can fight pathogens, an imbalance of oxidant/anti-oxidant activity can lead to harmful effects in our body known as oxidative stress. Various cellular organelles produce oxidative agents as well as anti-oxidants. The main oxidative stressors are classified under the free radical species; reactive oxygen species and reactive nitrogen species. On the other hand, superoxide dismutase, glutathione peroxidase, catalase and Glutathione are the main enzymatic mechanisms against oxidations. Gut microbiota with trillions of beneficial bacteria plays a considerable role in the production of anti-oxidants. Emerging evidence indicates an association between damaged intestinal flora and oxidative stress. Probiotics as beneficial bacteria are shown to restore damaged intestinal microbiota. Extensive evidence indicates the helpful effects of probiotics on the balance of anti-oxidant/oxidant agents. Since oxidative stressors play an important role in the development of some neurological disorders, intestinal microbiota modification and probiotic supplements are considered as suggested treatments to prevent or even relieve symptoms in the brain diseases. This review considers the beneficial effect of the gut and probiotic bacteria in either fighting the oxidative factors or producing the anti-oxidative biomarkers.

Effects of nano-curcumin on noise stress-induced hippocampus-dependent memory impairment: behavioral and electrophysiological aspects.

BACKGROUND: Noise pollution is one of the fundamental factors in the etiology of many disorders. Noise stress adversely affects cognitive behaviors and long-term potentiation (LTP), the candidate mechanism of learning and memory. In the present study, we examined the neuroprotective effects of nano-curcumin on behavioral and electrophysiological aspects of hippocampus-dependent memory in noise-exposed animals. METHODS: The stressed animals received either vehicle (ST) or nano-curcumin (NANO + ST) for 2 weeks. The control groups remained either intact (CON) or received nano-curcumin (NANO + CON). The ST and NANO + ST groups were exposed to daily noise for 2 weeks. The spatial memory was assessed in the Morris water maze. The LTP was investigated through field potential recording in the CA3-CA1 pathway of the hippocampus. Serum corticosterone level was measured at the end of the experiments. RESULTS: The ST group showed a lower cognitive function and suppressed LTP compared to the CON group. The nano-curcumin treatment improved the maze navigation and LTP induction compared to the ST group. While the stress exposure elevated the serum level of corticosterone in the ST animals, nano-curcumin treatment reduced it. CONCLUSIONS: The nano-curcumin treatment restores impaired behavioral and electrophysiological aspects of learning and memory in the noise-exposed animals. The plasma corticosterone levels may be associated with changes in cognitive behavior and synaptic plasticity.

Low-dose ethanol ameliorates amnesia induced by a brief seizure model: the role of NMDA signaling.

Objective: The present study aimed to evaluate the ameliorative effect of low-dose ethanol (Eth) on amnesia induced by a brief seizure model and the role of N-methyl D-aspartate (NMDA) signaling in this event. Materials and Methods: Four groups of rats (total number = 36; n = 9, each group) were used: control, Eth (0.5 g/kg/i.p.), pentylenetetrazole (PTZ) (60 mg/kg/i.p.), and Eth+PTZ. Eth was administered for 6 days before the single injection of PTZ, at minute dose that cannot induce memory impairment. The consequences of Eth pretreatment, coadministered with PTZ, were studied in an inhibitory avoidance (IA) memory model. The PTZ was injected 30 min prior to the IA memory test. Thereafter, locomotion, liver enzymes, and the Real-time PCR for NR1 subunit of NMDA receptor were studied. The statistical analyses were performed using the parametric/nonparametric ANOVA and the post-hoc tests. Results: Our findings revealed that Eth pretreatment significantly improved the IA memory impairment induced by PTZ (P < 0.001), and indicated no change in locomotion and serum ALT, but significantly differed for AST between the PTZ and PTZ groups (P = < 0.05). The Real-time PCR results indicate the decreased NR1 mRNA expression in Eth and PTZ groups and the increased NR1 mRNA expression in Eth+PTZ group, compared to the control group (P < 0.001); however, the NR1 mRNA expression was increased in the Eth+PTZ group, compared to PTZ group (P < 0.001). Conclusion: The present study provides evidence that the low-dose Eth can improve the amnesia induced by a brief seizure model presumably via NMDA signaling in a rat.

Effect of probiotic supplementation on seizure activity and cognitive performance in PTZ-induced chemical kindling.

Epilepsy is one of the most common neurological disorders that severely affect life quality of many people worldwide. Ion transport in the neuronal membrane, inhibitory-excitatory mechanisms, and regulatory modulator systems have been implicated in the pathogenesis of epilepsy. A bidirectional communication is proposed between brain and gut where the brain modulates the gastrointestinal tract, and the gut can affect brain function and behavior. The gut microbiome takes an important role in health and disease where dysbiosis is involved in several neurological disorders. Probiotics as living microorganisms are beneficial to humans and animals when adequately administered. In the present work, we evaluated the effect of a probiotic bacteria mixture on seizure activity, cognitive function, and gamma-aminobutyric acid (GABA), nitric oxide (NO), malondealdehyde (MDA), and total antioxidant capacity (TAC) level of the brain tissue in the pentylenetetrazole (PTZ)-induced kindled rats. The Racine score and performance in water maze were considered as indices of the epileptic severity and the spatial learning and memory, respectively. We found that the probiotic supplementation substantially reduces seizure severity so that almost no probiotic-treated animals showed full kindling. The oral bacteriotherapy partially improved the spatial learning and memory in the kindled rats. The intervention decreased NO and MDA and increased TAC concentration of the brain. The probiotic treatment also increased the inhibitory neurotransmitter GABA. Our findings are the first preclinical report to show positive effect of probiotic bacteria on seizure-induced neurological disorders. Further investigation is required to answer the questions raised about the probable mechanisms involved.

Corrigendum: Does Severity of Alzheimer's Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial.

[This corrects the article DOI: 10.3389/fneur.2018.00662.].

Does Severity of Alzheimer's Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial.

Alzheimer's disease (AD) is associated with cognitive dysfunction. Evidence indicates that gut microbiota is altered in the AD and, hence, modifying the gut flora may affect the disease. In the previous clinical research we evaluated the effect of a probiotic combination on the cognitive abilities of AD patients. Since, in addition to pathological disorders, the AD is associated with changes in oxidant/antioxidant and inflammatory/anti-inflammatory biomarkers, the present work was designed to evaluate responsiveness of the inflammatory and oxidative biomarkers to the probiotic treatment. The control (CON) and probiotic (PRO) AD patients were treated for 12 weeks by the placebo and probiotic supplementation, respectively. The patients were cognitively assessed by Test Your Memory (TYM = 50 scores). Also serum concentrations of nitric oxide (NO), glutathione (GSH), total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-2' -deoxyguanosine (8-OHdG) and cytokines (TNF-a, IL-6, and IL-10) were measured. The cognitive test and the serum biomarkers were assessed pre- and post-treatment. According to TYM test 83.5% of the patients showed severe AD. The CON (12.86% ± 8.33) and PRO (-9.35% ± 16.83) groups not differently scored the cognitive test. Not pronounced change percent was found in the serum level of TNF-α (1.67% ± 1.33 vs. -0.15% ± 0.27), IL-6 (0.35% ± 0.17 vs. 2.18% ± 0.15), IL-10 (0.05% ± 0.10 vs. -0.70% ± 0.73), TAC (0.07% ± 0.07 and -0.06% ± 0.03), GSH (0.08% ± 0.05 and 0.04% ± 0.03) NO (0.11% ± 0.06 and 0.05% ± 0.09), MDA (-0.11% ± 0.03 and -0.17% ± 0.03), 8-OHdG (43.25% ± 3.01 and 42.70% ± 3.27) in the CON and PRO groups, respectively. We concluded that the cognitive and biochemical indications in the patients with severe AD are insensitive to the probiotic supplementation. Therefore, in addition to formulation and dosage of probiotic bacteria, severity of disease and time of administration deeply affects results of treatment.