Therapeutic Potentials of MicroRNA-126 in Cerebral Ischemia.

Stroke is a leading cause of death and disability worldwide. It is among the most common neurological disorders with an 8-10% lifetime risk. Ischemic stroke accounts for about 85% of all strokes and damages the brain tissue via various damaging mechanisms. Following cerebral ischemia, the disrupted blood-brain barrier (BBB) leads to cerebral edema formation caused by activation of oxidative stress, inflammation, and apoptosis, targeting primarily endothelial cells. Activation of the protective mechanisms might favor fewer damages to the neural tissue. MicroRNA (miR)-126 is an endothelial cell-specific miR involved in angiogenesis. MiR-126 orchestrates endothelial progenitor cell functions under hypoxic conditions and could inhibit ischemia-induced oxidative stress and inflammation. It alleviates the BBB disruption by preventing an augment in matrix metalloproteinase level and halting the decrease in the junctional proteins, including zonula occludens-1 (ZO-1), claudin-5, and occludin levels. Moreover, miR-126 enhances post-stroke angiogenesis and neurogenesis. This work provides a therapeutic perspective for miR-126 as a new approach to treating cerebral ischemia.

The benefits of grape seed extract in neurological disorders and brain aging.

Common neurological disorders, including neurodegenerative diseases, stroke, epilepsy, autism and psychiatric disorders, affect many people worldwide and threaten their lives and health by inducing movement disorders, behavioral disorders, or a combination of both. Oxidative stress and neuroinflammation play a central role in neuronal damage and neurological diseases induction and progression. In addition, protein homeostasis (proteostasis) impairment occurs in many neurodegenerative diseases, which plays a critical role in the progression of the pathology. Grape seed contains several flavonoids and non-flavonoids and exerts potent antioxidant and anti-inflammatory effects. In addition, polyphenols and flavanols can maintain cellular proteostasis. Since impaired proteostasis is closely involved in all amyloid diseases, particularly neurodegenerative diseases, grape seeds extract can be a valuable therapeutic agent. Therefore, this review discusses the protective and therapeutic mechanisms of grape seed against neurological disorders and, in the end, links GSE to microRNAs as future therapeutic developments.

Roles of the miR-155 in Neuroinflammation and Neurological Disorders: A Potent Biological and Therapeutic Target.

Neuroinflammation plays a crucial role in the development and progression of neurological disorders. MicroRNA-155 (miR-155), a miR is known to play in inflammatory responses, is associated with susceptibility to inflammatory neurological disorders and neurodegeneration, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis as well as epilepsy, stroke, and brain malignancies. MiR-155 damages the central nervous system (CNS) by enhancing the expression of pro-inflammatory cytokines, like IL-1ß, IL-6, TNF-α, and IRF3. It also disturbs the blood-brain barrier by decreasing junctional complex molecules such as claudin-1, annexin-2, syntenin-1, and dedicator of cytokinesis 1 (DOCK-1), a hallmark of many neurological disorders. This review discusses the molecular pathways which involve miR-155 as a critical component in the progression of neurological disorders, representing miR-155 as a viable therapeutic target.

Neuroprotective effects of the fractions of Ocimum basilicum in seizures induced by pentylenetetrazole in mice.

Objective: Neuroprotective and antioxidant effects of Ocimum basilicum (O. basilicum) against pentylenetetrazole (PTZ)-induced seizures were investigated. Materials and Methods: Mice were divided as follows: (Group 1) Control, (Group 2) PTZ, (Groups 3-5) 50,100 and 200 mg/kg hydro-ethanolic (HE) extract, and (Groups 6-8) 200 mg/kg ethyl-acetate (EAF), N-hexane (NHF) and water (WF) fractions. Minimal clonic seizures (MCS) and generalized tonic-clonic seizures (GTCS) latencies were measured. Biochemical and histological studies were done. Results: MCS and GTCS latency in HE groups were longer than the PTZ group (p<0.05 to p<0.001). EAF and NHF prolonged the onset of MCS and GTCS (p<0.001). PTZ increased malondialdehyde (MDA) and dark neuron (DN) production while decreased thiol, catalase (CAT) and superoxide dismutase (SOD) (p<0.05 to p<0.001). Pre-treatment by HE and all fractions of the plant attenuated MDA and DN while increased thiol, CAT and SOD (p<0.01 to p<0.001). Conclusion: EAF and NHF had anticonvulsant properties. The extract and fractions protected the brain from PTZ-induced oxidative damages and showed neuroprotective effects.

Targeting miR-21 in spinal cord injuries: a game-changer?

Spinal cord injury (SCI) is a devastating neurological state causing physical disability, psychological stress and financial burden. SCI global rate is estimated between 250,000 and 500,000 individuals every year, of which 60% of victims are young, healthy males between 15 and 35 years. A variety of pathological conditions such as neuroinflammation, mitochondrial dysfunction, apoptosis, glial scar formation, blood-spinal cord barrier disruption, and angiogenesis disruption occur after SCI leading to a limitation in recovery. MicroRNAs (miRs) are endogenous and non-coding RNAs consisting of 22 nucleotides that regulate 60% of all human genes and involve several normal physiological processes and pathological conditions. miR-21 is among the most highly expressed miRs and its expression has been shown to increase one day after SCI and this elevation is sustained up to 28 days after injury. Overexpression of miR-21 exerts many protective effects against SCI by inhibiting neuroinflammation, improving blood-spinal cord barrier function, regulating angiogenesis, and controlling glial scar formation. It also exhibits anti-apoptotic effects in SCI by down-regulating the expression of PTEN, Spry2, and PDCD4. This review provides a novel therapeutic perspective for miR-21 in SCI.

A focus on natural products for preventing and cure of mitochondrial dysfunction in Parkinson's disease.

Mitochondria are considered the only source of energy production within cells. This organelle is vital for neural function and survival by producing energy (adenosine triphosphate (ATP)) and regulating intracellular calcium. Mitochondrial dysfunction, which significantly contributes to both idiopathic and familial types of Parkinson's disease (PD), depletes cellular energy, disrupts homeostasis, and induces oxidative stress, leading to cell death. In recent years several natural products have been discovered to be protective against mitochondrial dysfunction. This review discusses the role of mitochondria in the progression of PD to define the path for using natural products to prevent and/or cure PD.

MicroRNA-22: a Novel and Potent Biological Therapeutics in Neurological Disorders.

MicroRNAs (miRs) are regulatory RNAs with 18-25 nucleotides lengths involved in various biological processes. Some miRs, including miR-22, play an essential role in regulating neurological disorders. MiR-22 is a brain-enriched regulatory element involved in angiogenesis, energy supply, adjustment of ionic channels, and suppression of malignant cell proliferation, migration, and invasion. This article discusses the protective and therapeutic effects of miR-22 on neurological diseases and injuries, including cerebral ischemia, neurodegenerative diseases, epilepsy, and brain malignancies. We also correlated miR-22 with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), panic disorders, schizophrenia, neural tube defect (anencephaly), and traumatic brain injury. This work provides a therapeutic perspective for miR-22 as a new approach in treating neurological disorders.

Maternal exposure to silicon dioxide nanoparticles reduces hippocampal neurogenesis and synaptogenesis and induces neurodegeneration in rat offspring hippocampus.

Silicon dioxide nanoparticles (SiO2-NPs) are among the most widely used nanoparticles because of their chemical-physical properties. Since most brain maturation occurs in the neonatal period in humans and many mammals, it is important to understand how NPs may affect this process. This study tested the hypothesis that SiO2-NPs from treated dams could affect the hippocampus of neonatal rats during lactation. Twenty-four pregnant rats, after delivery, were divided into three groups of control, SiO2-NPs (25 mg/kg) and SiO2-NPs (100 mg/kg). The rats were treated from 2nd to 21st days post-delivery by gavage and the effects of these NPs were evaluated in the offspring's hippocampi to reveal the effects of maternal exposure to SiO2-NPs during lactation on the offspring's hippocampi. The offspring in the SiO2-NPs groups had higher malondialdehyde concentration and lower antioxidant activity in the hippocampi than the non-treated control group. The mean number of doublecortin positive (DCX+) cells and synaptophysin expression in the hippocampi of the SiO2-NPs groups were significantly lower than the control group, whereas the mean number of dark neurons was significantly higher. Also, animals in the SiO2-NPs groups had a weak cognitive performance in adulthood. In conclusion, maternal exposure to SiO2-NPs via breastfeeding could affect offspring's hippocampal neurogenesis and synaptogenesis, leading to impaired cognitive performance.

Grape seed extract effects on hippocampal neurogenesis, synaptogenesis and dark neurons production in old mice. Can this extract improve learning and memory in aged animals?

BACKGROUND: During the elderly, hippocampal neurogenesis and synaptogenesis reduce and dark neurons (DNs) increase, leading to cognitive impairment. It is believed that natural products can protect the neural cells and system by protecting from damages or promoting regeneration. Therefore, the effects of grape seed extract (GSE) on the hippocampus of aged mice were investigated in this study. METHODS: twelve old mice were divided into two groups of control and GSE. Animals in the GSE group received 300 mg/kg of GSE for eight weeks via gavage. At the end of treatment, cognition performance was evaluated by Morris water maze (MWM) and passive avoidance tests. Hippocampal neurogenesis, synaptogenesis and DNs production were evaluated with immunohistochemistry and histological evaluations on 5-micron coronal tissue sections. RESULTS: The hippocampal mean number of double cortin positive cells (DCX+) per unit area, as well as synaptophysin expression in the GSE group, were significantly higher than the control group (p < 0.01). The frequency of DNs in the GSE group was lower than the control group (p < 0.05). Behavioral tests showed that GSE improves memory and learning performance. CONCLUSION: Consuming GSE in the elderly can potentially alleviate the age-related reduction of hippocampal neurogenesis and synaptogenesis. It is also able to decrease hippocampal DNs production and increase memory and learning.

Hippocampal toxicity of metal base nanoparticles. Is there a relationship between nanoparticles and psychiatric disorders?

Metal base nanoparticles are widely produced all over the world and used in many fields and products such as medicine, electronics, cosmetics, paints, ceramics, toys, kitchen utensils and toothpastes. They are able to enter the body through digestive, respiratory, and alimentary systems. These nanoparticles can also cross the blood brain barrier, enter the brain and aggregate in the hippocampus. After entering the hippocampus, they induce oxidative stress, neuro-inflammation, mitochondrial dysfunction, and gene expression alteration in hippocampal cells, which finally lead to neuronal apoptosis. Metal base nanoparticles can also affect hippocampal neurogenesis and synaptic plasticity that both of them play crucial role in memory and learning. On the one hand, hippocampal cells are severely vulnerable due to their high metabolic activity, and on the other hand, metal base nanoparticles have high potential to damage hippocampus through variety of mechanisms and affect its functions. This review discusses, in detail, nanoparticles' detrimental effects on the hippocampus in cellular, molecular and functional levels to reveal that according to the present information, which types of nanoparticles have more potential to induce hippocampal toxicity and psychiatric disorders and which types should be more evaluated in the future studies.

Developmental regulation and lateralization of N-methyl-d-aspartate (NMDA) receptors in the rat hippocampus.

N-methyl-d-aspartate receptors (NMDARs) are expressed abundantly in the brain and play a crucial role in the regulation of central nervous system (CNS) development, learning, and memory. During early neuronal development, NMDARs modulate neurogenesis, neuronal differentiation and migration, and synaptogenesis. The present study aimed to examine the developmental expression of NMDARs subunits, NR1 and NR2B, in the developing hippocampus of neonatal rats during the first two postnatal weeks. Fifty-four male offspring were randomly divided into three age groups, postnatal days (P) 0, 7, and 14. Real-time-PCR, western blotting, and immunohistochemistry (IHC) analyses were employed to examine and compare the hippocampal expression of the NMDA receptor subunits. The highest mRNA expression of NR1 and NR2B subunits was observed at P7, regardless of its laterality. The mRNA expression of both subunits in the right hippocampus was significantly higher than that of the left one at P0 and P7. Similarly, the highest protein level expression of NR1 and NR2B subunits was also observed at P7 in both sides hippocampi. Although the protein expression of NR1 was significantly higher on the right side in all studied days, the NR2B was significantly higher in the right hippocampus only at P7. The analysis of optical density (OD) has shown a marked increase in the distribution pattern of the NR1 and NR2B subunits at P7 in all hippocampal subregions. In conclusion, there is a marked right-left asymmetry in the expression of NR1 and NR2B subunits in the developing rat hippocampus, which might be considered as a probable mechanism for the lateral differences in the structure and function of the hippocampus in rats.

Cell and molecular toxicity of lanthanum nanoparticles: are there possible risks to humans?

Lanthanum nanoparticles are widely used in industry, agriculture, and biomedicine. Over 900 kg of lanthanum is annually released into the environment only in Europe, 50 times higher than the metals, mercury, and cadmium's environmental spread. Human health risk associated with long-term exposure to the abundant lanthanum nanoparticles is a concerning environmental issue. Due to lanthanum's ability to disrupt the main biological barriers and interrupt various cells' hemostasis, they seem to cause severe disruptions to various tissues. This review opens a new perspective regarding the cellular and molecular interaction of nanosized and ionic lanthanum with the possible toxicity on the nervous system and other tissues that would show lanthanum nanoparticles' potential danger to follow in toxicological science.

Neuroprotective effects of garlic extract on dopaminergic neurons of substantia nigra in a rat model of Parkinson's disease: motor and non-motor outcomes.

Parkinson's disease (PD) is a common and severe neurodegenerative disorder associated with a selective loss of dopaminergic neurons in substantia nigra pars compacta. The crucial role of oxidative stress and inflammation in PD onset and progression is evident. It has been proven that garlic extract (GE) protects the cells from oxidative stress, inflammation, mitochondrial dysfunction and apoptosis. That is, we aimed to investigate if GE reveals protective features on the preclinical model of PD. The study has been designed to evaluate both preventive (GE administered before 6-OHDA injection) and therapeutic (GE administered after 6-OHDA injection) effects of GE on the animal model. Forty male Wistar rats were divided into 4 groups including control, lesion, treatment I (received GE before 6-OHDA injection) and treatment II (received GE both before and after 6-OHDA injection). At the end of treatment, hanging, rotarod, open field and passive avoidance tests as well as immunohistochemistry were performed to evaluate the neuroprotective effects of garlic against PD. Our immunohistochemistry analysis revealed that the tyrosine hydroxylase positive cells (TH+) in GE treated groups were significantly higher (p˂0.001) than the lesion group. The motor deficiency significantly improved in hanging, rotarod, open-field and apomorphine-induced rotational tests. We observed an attenuation in memory impairment induced by PD on GE treated group. Therefore, we found that GE protects dopaminergic neurons in 6-OHDA-induced neurotoxicity and ameliorates movement disorders and behavioral deficits.

A link between nanoparticles and Parkinson's disease. Which nanoparticles are most harmful?

Nowadays, different kinds of nanoparticles (NPs) are produced around the world and used in many fields and products. NPs can enter the body and aggregate in the various organs including brain. They can damage neurons, in particular dopaminergic neurons in the substantia nigra (SN) and striatal neurons which their lesion is associated with Parkinson's disease (PD). So, NPs can have a role in PD induction along with other agents and factors. PD is the second most common neurodegenerative disease in the world, and in patients, its symptoms progressively worsen day by day through different pathways including oxidative stress, neuroinflammation, mitochondrial dysfunction, α-synuclein increasing and aggregation, apoptosis and reduction of tyrosine hydroxylase positive cells. Unfortunately, there is no effective treatment for PD. So, prevention of this disease is very important. On the other hand, without having sufficient information about PD inducers, prevention of this disease would not be possible. Therefore, we need to have sufficient information about things we contact with them in daily life. Since, NPs are widely used in different products especially in consumer products, and they can enter to the brain easily, in this review the toxicity effects of metal and metal oxide NPs have been evaluated in molecular and cellular levels to determine potential of different kinds of NPs in development of PD.

Developmental regulation and lateralisation of the α7 and α4 subunits of nicotinic acetylcholine receptors in developing rat hippocampus.

The purpose of this study was to describe the distinct regional distribution patterns of expression of the α7 and α4 subunits of nicotinic acetylcholine receptors (nAChRs) and their left-right lateralisation in the rat hippocampus during the first 2 weeks of postnatal (P) development. Eighteen male pups were randomly divided into three groups: P0, P7, and P14. After removing the newborn brains, real-time polymerase chain reaction, western blot, and immunohistochemistry techniques were used to evaluate expression of the receptors. Results indicated that the expression profile of these receptors were time- and spatially dependent. A significant increase was observed in the distribution of α7 and α4 nAChR subunits in the developing rat hippocampus from P0 to P7 (p < .001); however, there was a significant decrease from P7 to P14 (p < .05). As a spatial effect, the highest optical density (OD) was observed in the CA3 and CA2 regions of the hippocampus, while the lowest OD was in the dentate gyrus. Moreover, the distribution of α7 and α4 nAChR subunits in the left hippocampus was significantly higher than their counterparts in the right (p < .05). From these data, the expression patterns of α7 and α4 nAChR subunits exhibited left-right asymmetry in the developing rat hippocampus.

Developmental regulation and lateralization of GABA receptors in the rat hippocampus.

GABA is the chief inhibitory neurotransmitter in the adult brain. However, in the developing brain it acts as an excitatory transmitter causing depolarization. Thereby, activates calcium-dependent processes that are crucial for brain development. Accordingly, GABA receptors have the great role in the brain development, especially in the area with persisting neurogenesis such as hippocampus. The present study investigated the development and lateralization of two important subunits of GABA receptors, GABAAα1 and GABAB1, in the developing rat hippocampus during the neurogenesis-active period, at the first two postnatal weeks. Real-time PCR, western blot and immunohistochemistry were used. We found that the mRNA and protein of these GABA receptor subunits have already been expressed at birth and significantly increased at postnatal day (P) 7, and also at P14. Also, regarding the optical densities of GABAAα1 and GABAB1 expressing hippocampal cells, we found a significant increase in the distribution pattern of these subunits in the all hippocampal subregions on day 14 after birth. The highest optical density of GABAAα1 was observed in the CA3, and GABAB1 in the CA2. Nevertheless, our results did not show a significant laterality differences in the expression of these subunits. Regarding the crucial role of GABA receptors in the hippocampus development; they probably have the same effects on development of the rat hippocampus on both sides.

The effect of titanium dioxide nanoparticles on mice midbrain substantia nigra.

OBJECTIVES: Widely used Titanium dioxide nanoparticles (TiO2) enter into the body and cause various organ damages. Therefore, we aimed to study the effect of TiO2 on the substantia nigra of midbrain. MATERIALS AND METHODS: 40 male BALB/c mice were randomly divided into five groups: three groups received TiO2 at doses of 10, 25, and 50 mg/kg, the fourth group received normal saline for 45 days by gavage, and control group (without intervention). Then, Motor tests including pole and hanging tests were done to investigate motor disorders. The animal brain was removed for histological purposes. Accordingly, immunohistochemistry was performed to detect tyrosine hydroxylase positive cells, and then toluidine blue staining was done to identify dark neurons in the substantia nigra. Eventually, the total number of these neurons were counted using stereological methods in different groups. RESULTS: The results showed that the time recorded for mice to turn completely downward on the pole in the TiO2-50 group increased and also the time recorded for animals to hang on the wire in the hanging test significantly decreased (P<0.05) in comparison with other groups. Also, the average number of tyrosine hydroxylase positive neurons in TiO2-25 and TiO2-50 groups significantly decreased as compared to the TiO2-10 and control groups (P<0.05). The total number of dark neurons in the TiO2-25 and TiO2-50 groups was substantially higher than the TiO2-10, control and normal saline groups (P<0.05). CONCLUSION: Our findings indicated that TiO2, depending on dose, can cause the destruction of dopaminergic neurons and consequently increase the risk of Parkinson's disease.