Neuroprotection In Rats Research Articles

Effect of ethanol extract of nigella sativa L seeds and propofol on BDNF protein level as neuroplasticity and neuroprotection of traumatic brain injury in rats

Background Traumatic brain injury (TBI) is a change in brain function or evidence of brain pathology caused by external mechanical forces. Brain Derived Neurotrophic Factor (BDNF) is a neurotropin that functions as a neuron protective. Nigella sativa L is reported to have an antioxidant effect, administration of Nigella Sativa L to rats treated with ischemia-reperfusion brain injury. Propofol is an anesthetic agent frequently used intravenously in the management of TBI. The effect of propofol on brain tissue after TBI may be neuroprotective. We aimed to compare the potential of Nigella sativa L and propofol as neuroplasticity and neuroprotection in rats with TBI. Methods This was a laboratory experimental animal model with the post-test only control group design, namely measuring the effect of treatment by comparing the five groups of rats consisting of 30 rats. BDNF levels in rat brain tissue were collected at day 7 of treatment and measured by ELISA. Results The average BDNF protein levels per group, namely G1 (221,243 pg/mL), G2 (172,139 pg/mL), G3 (255,483 pg/mL), G4 (227,089 pg/mL), and G5 (272,603 pg/mL) respectively. Based on the ANOVA statistic, p-value = 0.032 (there was a significant difference between groups), with the Levene Test (0.077) or having variance between the same groups, sequentially the difference in average BDNF protein levels of the five groups is G5>G3>G4>G1>G2, meaning that the combination of Nigella sativa and propofol has more potential to increase BDNF protein levels than Nigella sativa, and Nigella sativa has more potential than propofol. Conclusion We concluded that both nigella sativa and propofol have the potential to increase BDNF protein levels. Nigella Sativa L had a better effect than propofol in repairing damaged neuron cells (neuroplasticity) and increasing BDNF protein levels (neuroprotection) for 7 days of administration in rat traumatic brain injury.

Scorpion venom heat-resistant synthesized peptide ameliorates epileptic seizures and imparts neuroprotection in rats mediated by NMDA receptors

Finding new and effective natural products for designing antiepileptic drugs is highly important in the scientific community. The scorpion venom heat-resistant peptide (SVHRP) was purified from Buthus martensii Karsch scorpion venom, and subsequent analysis of the amino acid sequence facilitated the synthesis of a peptide known as scorpion venom heat-resistant synthesis peptide (SVHRSP) using a technique for peptide synthesis. Previous studies have demonstrated that the SVHRSP can inhibit neuroinflammation and provide neuroprotection. This study aimed to investigate the antiepileptic effect of SVHRSP on both acute and chronic kindling seizure models by inducing seizures in male rats through intraperitoneal administration of pentylenetetrazole (PTZ). Additionally, an N-methyl-D-aspartate (NMDA)-induced neuronal injury model was used to observe the anti-excitotoxic effect of SVHRSP in vitro. Our findings showed that treatment with SVHRSP effectively alleviated seizure severity, prolonged latency, and attenuated neuronal loss and glial cell activation. It also demonstrated the prevention of alterations in the expression levels of NMDA receptor subunits and phosphorylated p38 MAPK protein, as well as an improvement in spatial reference memory impairment during Morris water maze (MWM) testing in PTZ-kindled rats. In vitro experiments further revealed that SVHRSP was capable of attenuating neuronal action potential firing, inhibiting NMDA receptor currents and intracellular calcium overload, and reducing neuronal injury. These results suggest that the antiepileptic and neuroprotective effects of SVHRSP may be mediated through the regulation of NMDA receptor function and expression. This study provides new insight into therapeutic strategies for epilepsy.

Effect of ethanol extract of nigella sativa L seeds and propofol on BDNF protein level as neuroplasticity and neuroprotection of traumatic brain injury in rats

Background Traumatic brain injury (TBI) is a change in brain function or evidence of brain pathology caused by external mechanical forces. Brain Derived Neurotrophic Factor (BDNF) is a neurotropin that functions as a neuron protective. Nigella sativa L is reported to have an antioxidant effect, administration of Nigella Sativa L to rats treated with ischemia-reperfusion brain injury. Propofol is an anesthetic agent frequently used intravenously in the management of TBI. The effect of propofol on brain tissue after TBI may be neuroprotective. We aimed to compare the potential of Nigella sativa L and propofol as neuroplasticity and neuroprotection in rats with TBI. Methods This was a laboratory experimental animal model with the post-test only control group design, namely measuring the effect of treatment by comparing the five groups of rats consisting of 30 rats. BDNF levels in rat brain tissue were collected at day 7 of treatment and measured by ELISA. Results The average BDNF protein levels per group, namely G1 (221,243 pg/mL), G2 (172,139 pg/mL), G3 (255,483 pg/mL), G4 (227,089 pg/mL), and G5 (272,603 pg/mL) respectively. Based on the ANOVA statistic, p-value = 0.032 (there was a significant difference between groups), with the Levene Test (0.077) or having variance between the same groups, sequentially the difference in average BDNF protein levels of the five groups is G5>G3>G4>G1>G2, meaning that the combination of Nigella sativa and propofol has more potential to increase BDNF protein levels than Nigella sativa, and Nigella sativa has more potential than propofol. Conclusion We concluded that both nigella sativa and propofol have the potential to increase BDNF protein levels. Nigella Sativa L had a better effect than propofol in repairing damaged neuron cells (neuroplasticity) and increasing BDNF protein levels (neuroprotection) for 7 days of administration in rat traumatic brain injury.

Neuroprotective effects of exosomes derived from bone marrow mesenchymal stem cells treated by Musk Ketone on ischemic stroke

ObjectivesIschemic stroke (IS) is a leading cause of morbidity and mortality globally. This study aimed to investigate the role of exosomes (Exo) derived from bone marrow mesenchymal stem cells (BMSCs) treated with Musk Ketone (Mus treated-Exo) in the development of IS injury. MethodsBMSCs were pretreated with 10 μM Mus for 36 h, and Exo derived from these Mus-treated BMSCs (Mus-treated Exo) were extracted. Rats with middle cerebral artery occlusion (MCAO) were administered either 2 mg/kg of control Exo (Ctrl-Exo), 2 mg/kg of Mus treated-Exo, or 10 μM Mus. Neurological deficit and cerebral infarction in the MCAO rats were assessed utilizing neurological scores and TTC staining. Neuronal apoptosis, activation of microglia/macrophages, and inflammation were evaluated through TUNEL staining, immunofluorescence staining, and western blot analysis, respectively. ResultsOur findings revealed that Mus-treated Exo possessed a more pronounced neuroprotective effect on MCAO rats when compared to Ctrl-Exo and Mus treatment alone. Specifically, Mus treated-Exo effectively ameliorated neurological function, reduced the volume of cerebral infarction, and diminished hemispheric swelling in MCAO rats. Moreover, it inhibited neuronal apoptosis and activation of microglia/macrophages, promoted the expression of the anti-apoptotic protein Bcl-2 while decreasing the expression of pro-apoptotic protein Bax, Cleaved-caspase 3, and pro-inflammatory factors IL-6 and COX-2. ConclusionsThe findings imply that Mus treated-Exo could confer neuroprotection in rats affected by IS, potentially by attenuating apoptosis and neuroinflammation. The underlying mechanisms, however, warrant further investigation. Mus treated-Exo shows potential as a new therapeutic strategy for IS.

Unraveling the therapeutic potential of ginsenoside compound Mc1 in Alzheimer's disease: Exploring the role of AMPK/SIRT1/NF-κB signaling pathway and mitochondrial function.

Alzheimer's disease (AD) is a disabling neurodegenerating disorder characterized by chronic neuroinflammation, cognitive impairment and memory loss. Current treatment options for AD offer limited benefits, underscoring the urgent need for alternative therapeutics. Despite the promising effects of ginsenosides in neurodegenerative diseases, the therapeutic potential of ginsenoside compound Mc1 (GCMc1) in AD remains to be thoroughly investigated. This study aimed to investigate the therapeutic potential of GCMc1 in rats with AD and to elucidate the molecular mechanisms responsible for its effects. Alzheimer's disease was induced in Sprague Dawley rats through a single intra-cerebro-ventricular injection of amyloid-beta (Aβ)1-42 peptide. The animals were divided into 5 groups: a control group and 4 AD subgroups, with or without receiving 10 mg/kg of GCMc1 and/or 100 μg/kg of compound C intraperitoneally (ip.). Behavioral tests, mitochondrial function, inflammatory cytokines, and proteins expression were evaluated using the Morris water maze (MWM) test, fluorometry, enzyme-linked immunosorbent assay (ELISA), and immunoblotting techniques, respectively. Treatment with GCMc1 improved cognitive function, reduced hippocampal Aβ accumulation, and suppressed interleukin (IL)-1β, IL-10 and tumor necrosis factor alpha (TNF-α) levels. Ginsenoside compound Mc1 reduced mitochondrial reactive oxygen species (ROS) levels and membrane depolarization, increased adenosine triphosphate (ATP) levels, upregulated the expression of AMPK, PGC-1α and SIRT1 proteins, and downregulated the nuclear factor-kappa-B (NF-κB) expression. Importantly, co-administration of compound C, an AMPK inhibitor, attenuated the beneficial effects of GCMc1, suggesting the involvement of AMPK pathway in mediating GCMc1's neuroprotective effects. We showed that GCMc1 confers substantial neuroprotection in rats with AD by modulating the AMPK/SIRT1/NF-κB signaling pathway. These findings highlight the potential of GCMc1 as a promising therapeutic agent for AD treatment.

Postconditioning with D-limonene exerts neuroprotection in rats via enhancing mitochondrial activity

Abstract Objectives The key component of neuroprotection after cerebral ischemia–reperfusion (I–R) injury is mitochondrial improvement. By focusing on the function of mitochondrial biogenesis and ATP-sensitive potassium (mK–ATP) channels and inflammatory responses, the current study assessed the neuroprotective potentials of lemon essential oil, D-limonene (LIM), in rats with cerebral I–R injury. Methods In order to simulate cerebral I–R injury, Sprague Dawley rats (n=72) were subjected to a two h local ischemia induced by middle cerebral artery blockage, followed by a 24 h reperfusion period. Five minutes before starting reperfusion, rats were intraperitoneally given LIM at doses of 10 or 100 mg/kg. Cerebral infarct volume was assessed by triphenyl-tetrazolium chloride staining, brain activity by behavioral tests and mitochondrial function/biogenesis, as well as proinflammatory cytokines by fluorometry, immunoblotting and other related techniques. Results When compared to the untreated control group, the administration of LIM substantially and dose-dependently decreased cerebral infarct volumes and neurological deficits (p<0.01). I–R injury-induced alterations in mitochondrial membrane depolarization, mitochondrial reactive oxygen species (mitoROS), and superoxide dismutase (mnSOD), as well as inflammatory cytokines TNF-α, IL-6 and IL-1β, were all significantly reversed after treatment with LIM 100 mg/kg (p<0.01). Additionally, this dose of LIM increased the expression of mitochondrial biogenesis proteins PGC-1α, TFAM, and NRF1. Interestingly, blockage of mK–ATP channels by 5-hydoxydecanoate diminished the effects of LIM on cerebral positive endpoints, cytokines production, and mitochondrial function/biogenesis. Conclusions Thus, the strong neuroprotective effects of LIM-postconditioning were mediated by an increase in mK–ATP channel activity, which improved mitochondrial biogenesis and suppressed inflammatory responses.

Gut microbiota and transcriptome dynamics in every-other-day fasting are associated with neuroprotection in rats with spinal cord injury.

Every-other-day fasting (EODF) is a classical intermittent fasting (IF) mode with neuroprotective effects that promotes motor function recovery after spinal cord injury (SCI) in rats. However, its dynamic effects on the gut microbiota and spinal cord transcriptome remain unknown. In this study, 16S rRNA sequencing and RNA-seq analysis were used to investigate the effects of ad libitum (AL) and EODF dietary modes on the structural characteristics of rat gut microbiota in rats and the spinal cord transcriptome at various time points after SCI induction. Our results showed that both dietary modes affected the bacterial community composition in SCI rats, with EODF treatment inducing and suppressing dynamic changes in the abundances of potentially anti-inflammatory and pro-inflammatory bacteria. Furthermore, the differentially expressed genes (DEGs) enriched after EODF intervention in SCI rats were associated with various biological events, including immune inflammatory response, cell differentiation, protein modification, neural growth, and apoptosis. In particular, significant spatiotemporal differences were apparent in the DEGs associated with neuroprotection between the EODF and AL interventions. These DGEs were mainly focused on days 1, 3, and 7 after SCI. The relative abundance of certain genera was significantly correlated with DEGs associated with neuroprotective effects in the EODF-SCI group. Our results showed that EODF treatment may exert neuroprotective effects by modulating the transcriptome expression profile following SCI in rats. Furthermore, gut microbiota may be partially involved in mediating these effects.

Engeletin alleviates cerebral ischemia reperfusion-induced neuroinflammation via the HMGB1/TLR4/NF-κB network.

High-mobility group box1 (HMGB1) induces inflammatory injury, and emerging reports suggest that it is critical for brain ischemia reperfusion. Engeletin, a natural Smilax glabra rhizomilax derivative, is reported to possess anti-inflammatory activity. Herein, we examined the mechanism of engeletin-mediated neuroprotection in rats having transient middle cerebral artery occlusion (tMCAO) against cerebral ischemia reperfusion injury. Male SD rats were induced using a 1.5 h tMCAO, following by reperfusion for 22.5 h. Engeletin (15, 30 or 60 mg/kg) was intravenously administered immediately following 0.5 h of ischemia. Based on our results, engeletin, in a dose-dependent fashion, reduced neurological deficits, infarct size, histopathological alterations, brain edema and inflammatory factors, namely, circulating IL-1β, TNF-α, IL-6 and IFN-γ. Furthermore, engeletin treatment markedly reduced neuronal apoptosis, which, in turn, elevated Bcl-2 protein levels, while suppressing Bax and Cleaved Caspase-3 protein levels. Meanwhile, engeletin significantly reduces overall expressions of HMGB1, TLR4, and NF-κB and attenuated nuclear transfer of nuclear factor kappa B (NF-κB) p65 in ischemic cortical tissue. In conclusion, engeletin strongly prevents focal cerebral ischemia via suppression of the HMGB1/TLR4/NF-κB inflammatory network.

Intranasal Delivery of a Silymarin Loaded Microemulsion for the Effective Treatment of Parkinson’s Disease in Rats: Formulation, Optimization, Characterization, and In Vivo Evaluation

A mucoadhesive microemulsion of lipophilic silymarin (SLMMME) was developed to treat Parkinson's disease (PD). Optimization of the SLM microemulsion (ME) was performed using Central Composite Design (CCD). The composition of oil, surfactant, co-surfactant, and water was varied, as per the design, to optimize their ratio and achieve desirable droplet size, zeta potential, and drug loading. The droplet size, zeta potential, and drug loading of optimized SLMME were 61.26 ± 3.65 nm, -24.26 ± 0.2 mV, and 97.28 ± 4.87%, respectively. With the addition of chitosan, the droplet size and zeta potential of the developed ME were both improved considerably. In vitro cell toxicity investigations on a neuroblastoma cell line confirmed that SLMMME was non-toxic and harmless. In comparison to ME and drug solution, mucoadhesive ME had the most flow through sheep nasal mucosa. Further, the in vitro release showed significantly higher drug release, and diffusion of the SLM loaded in MEs than that of the silymarin solution (SLMS). The assessment of behavioral and biochemical parameters, as well as inflammatory markers, showed significant (p < 0.05) amelioration in their level, confirming the significant improvement in neuroprotection in rats treated with SLMMME compared to rats treated with naïve SLM.

3-Bromopyruvate, a caloric restriction mimetic, exerts a mitohormetic effect to provide neuroprotection through activation of autophagy in rats during aging.

In the present study, attempts have been made to evaluate the potential role of 3 Bromopyruvate (3-BP) a glycolytic inhibitor and a caloric restriction mimetic (CRM), to exert neuroprotection in rats during aging through modulation of autophagy. Young male rats (4 months), and naturally aged (22 months) male rats were supplemented with 3-BP (30mg/kg b.w., orally) for 28 days. Our results demonstrate a significant increase in the antioxidant biomarkers (ferric reducing antioxidant potential level, total thiol, superoxide dismutase, and catalase activities) and a decrease in the level of pro-oxidant biomarkers such as protein carbonyl after 3-BP supplementation in brain tissues. A significant increase in reactive oxygen species (ROS) was observed due to the mitohormetic effect of 3-BP supplementation in the treated rats. Furthermore, the 3-BP treatment also enhanced the activities of electron transport chain complexes I and IV in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuroprotective and aging marker genes. RT-PCR data revealed that 3-BP up-regulated the expression of autophagy markers genes (Beclin-1 and LC3 β), sirtuin-1, and neuronal marker gene (NSE), respectively in the aging brain. The results suggest that 3-BP induces a mitohormetic effect through the elevation of ROS which reinforces defensive mechanism(s) targeted at regulating autophagy. These findings suggest that consistently low-dose 3-BP may be beneficial for neuroprotection during aging and age-related disorders.

Nitric Oxide Involvement in Cardiovascular Dysfunctions of Parkinson Disease.

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra, causing motor changes. In addition to motor symptoms, non-motor dysfunctions such as psychological, sensory and autonomic disorders are recorded. Manifestations related to the autonomic nervous system include the cardiovascular system, as postural hypotension, postprandial hypotension, and low blood pressure. One of the mediators involved is the nitric oxide (NO). In addition to the known roles such as vasodilator, neuromodulator, NO acts as an important mediator of the immune response, increasing the inflammatory response provoked by PD in central nervous system. The use of non-specific NOS inhibitors attenuated the neurodegenerative response in animal models of PD. However, the mechanisms by which NO contributes to neurodegeneration are still not well understood. The literature suggest that the contribution of NO occurs through its interaction with superoxides, products of oxidative stress, and blocking of the mitochondrial respiratory chain, resulting in neuronal death. Most studies involving Parkinsonism models have evaluated brain NO concentrations, with little data available on its peripheral action. Considering that studies that evaluated the involvement of NO in the neurodegeneration in PD, through NOS inhibitors administration, showed neuroprotection in rats, it has prompted new studies to assess the participation of NOS isoforms in cardiovascular changes induced by parkinsonism, and thus to envision new targets for the treatment of cardiovascular disorders in PD. The aim of this study was to conduct a literature review to assess available information on the involvement of nitric oxide (NO) in cardiovascular aspects of PD.

Trihydroxyethyl Rutin Provides Neuroprotection in Rats With Cervical Spinal Cord Hemi-Contusion.

Objective: To investigate the neuroprotective effects of trihydroxyethyl rutin in rats with cervical spinal cord hemi-contusion.Methods: Adult male Sprague–Dawley rats were subjected to hemi-contusion at a stroke depth of 1.2 mm, and then intraperitoneally injected with 50 or 100 mg/kg trihydroxyethyl rutin per day for 12 weeks (T50 and T100 groups, respectively). Changes in somatosensory evoked potentials (SEPs), motor evoked potentials (MEPs), and behavior were continuously monitored. At 12 weeks post-injury, immunohistochemical staining was performed to assess changes in cervical spinal cord microvascular morphology. Magnetic resonance imaging (MRI) scans were performed to examine end-stage injury in the cervical spinal cord, and Eriochrome cyanine-stained slices of spinal cord tissue were evaluated for injury.Results: There were no significant differences in biomechanical parameters among the spinal cord injury, T50 and T100 rat groups. At 3 days-post-injury, there was a significant decrease in grip strength. At 12 weeks post-injury, grip strength recovery was significantly better in the T50 and T100 groups than in the injury group. Compared with the injury group, the total limb placement frequency was significantly higher in the T50 group at 2, 4, 6, 10, and 12 weeks post-injury and in the T100 group at 2, 6, 8, and 10 weeks post-injury. Ipsilateral SEPs and MEPs were dynamic, increasing in latency and decreasing in amplitude in the injury compared with sham group. MRI scanning demonstrated that the coronal, sagittal, and transversal lesion areas were smaller in the T50 and T100 groups than in the injury group. Microvascular density showed a greater reduction in the injury group compared with the T50 and T100 groups. Eriochrome cyanine staining showed that the ipsilateral side, residual parenchyma, and gray matter areas were larger in the T50 and T100 groups than in the injury group.Conclusion: Trihydroxyethyl rutin exhibits robust neuroprotective effects, improving limb motor function and nerve electrophysiological parameters after spinal cord injury, maintaining microvascular density, and reducing the area of injury and degree of demyelination.

Retraction Statement.

Retraction Statement.

Initiation of L-DOPA Treatment After Detection of Diabetes-Induced Retinal Dysfunction Reverses Retinopathy and Provides Neuroprotection in Rats

PurposeL-DOPA treatment initiated at the start of hyperglycemia preserves retinal and visual function in diabetic rats. Here, we investigated a more clinically relevant treatment strategy in which retinal and visual dysfunction designated the beginning of the therapeutic window for L-DOPA treatment.MethodsSpatial frequency thresholds using optomotor response and oscillatory potential (OP) delays using electroretinograms were compared at baseline, 3, 6, and 10 weeks after streptozotocin (STZ) between diabetic and control rats. L-DOPA/carbidopa treatment (DOPA) or vehicle was delivered orally 5 days per week beginning at 3 weeks after STZ, when significant retinal and visual deficits were measured. At 10 weeks after STZ, retinas were collected to measure L-DOPA, dopamine, and 3,4-dihydroxyphenylacetic acid (DOPAC) levels using high-performance liquid chromatography.ResultsSpatial frequency thresholds decreased at 6 weeks in diabetic vehicle rats (28%), whereas diabetic DOPA rats had stable thresholds (<1%) that maintained to 10 weeks, creating significantly higher thresholds compared with diabetic vehicle rats (P < 0.0001). OP2 implicit times in response to dim, rod-driven stimuli were decreased in diabetic compared with control rats (3 weeks, P < 0.0001; 10 weeks, P < 0.01). With L-DOPA treatment, OP2 implicit times recovered in diabetic rats to be indistinguishable from control rats by 10 weeks after STZ. Rats treated with L-DOPA showed significantly increased retinal L-DOPA (P < 0.001) and dopamine levels (P < 0.05).ConclusionsL-DOPA treatment started after the detection of retinal and visual dysfunction showed protective effects in diabetic rats.Translational RelevanceEarly retinal functional deficits induced by diabetes can be used to identify an earlier therapeutic window for L-DOPA treatment which protects from further vision loss and restores retinal function.

Apoptosis inhibition is involved in improvement of sevoflurane-induced cognitive impairment following normobaric hyperoxia preconditioning in aged rats.

Sevoflurane, a commonly used anesthetic agent has been confirmed to induce cognitive impairment in aged rats. Normobaric hyperoxia preconditioning has been demonstrated to induce neuroprotection in rats. The present study aimed to determine whether normobaric hyperoxia preconditioning could ameliorate cognitive deficit induced by sevoflurane and the possible mechanism by which it may exert its effect. A total of 66, 20-month-old male Sprague-Dawley rats were randomly divided into 3 groups (n=22 each): Rats in the control (C) and sevoflurane anesthesia (S) groups received no normobaric hyperoxia preconditioning before sevoflurane exposure, rats in the normobaric hyperoxia pretreatment (HO) group received normobaric hyperoxia preconditioning before sevoflurane exposure (95% oxygen for 4 continuous h daily for 6 consecutive days). The anesthesia rats (S and HO groups), were exposed to 2.5% sevoflurane for 5 h, while the sham anesthesia rats (C group) were exposed to no sevoflurane. The neurobehavioral assessment was performed using a Morris water maze test, the expressions of the apoptosis proteins were determined using western blot analysis, and the apoptosis rate and cytosolic calcium concentration were measured by flow cytometry. Normobaric hyperoxia preconditioning improved prolonged escape latency and raised the number of platform crossings induced by sevoflurane in the Morris water maze test, increased the level of bcl-2 protein, and decreased the level of bax and active caspase-3 protein, the apoptosis rate and cytosolic calcium concentration in the hippocampus 24 h after sevoflurane exposure. The findings of the present study may imply that normobaric hyperoxia preconditioning attenuates sevoflurane-induced spatial learning and memory impairment, and this effect may be partly related to apoptosis inhibition in the hippocampus. In conclusion, normobaric hyperoxia preconditioning may be a promising strategy against sevoflurane-induced cognitive impairment by inhibiting the hippocampal neuron apoptosis.

Identification of candidate genes and pathways in dexmedetomidine-induced neuroprotection in rats using RNA sequencing and bioinformatics analysis.

Traumatic brain injury (TBI) is a major cause of disability worldwide, without definitive and effective intervention. Dexmedetomidine (DEX) has a neuroprotective effect against TBI; however, the detailed mechanism underlying this effect remains unclear. Ten male Sprague Dawley rats were used to establish a TBI model. The rats were randomly divided into two groups: the TBI group (TBI, control group) and the DEX treatment group (DEX). The next day, the neurological function of the rats were evaluated by the modified neurological severity score (mNSS). Then, the rats were sacrificed, and RNA sequencing was performed to identify differentially expressed messenger RNAs (mRNAs) and microRNAs (miRNAs) in brain tissue samples. Additionally, we performed a bioinformatics analysis to explore the candidate genes and pathways that might play important roles in DEX-induced neuroprotection. The most significantly differentially expressed miRNAs and possible hub genes were validated by quantitate reverse transcription-polymerase chain reaction (qRT-PCR) using more samples. In the DEX group, 517 mRNAs (352 up-regulated and 165 down-regulated) and 35 miRNAs (18 up-regulated and 17 down-regulated) were differentially expressed compared to the TBI group. Gene Ontology analysis revealed the up-regulated mRNAs to be significantly enriched in microtubule-based movement or processes, microtubule and tubulin binding. Kyoto Encyclopedia of Genes and Genomes analysis showed that these up-regulated mRNAs were significantly enriched in the B-cell receptor signaling pathway as well as the cell cycle pathway. Also, Lyn and Cdk1 were found to be associated with the B-cell receptor signaling and cell cycle pathways, respectively. Furthermore, the down-regulated miRNAs were significantly enriched in cellular components, although no significant Gene Ontology terms or KEGG pathways were found for the down-regulated mRNAs or up-regulated miRNAs. Differentially expressed mRNAs and miRNAs were identified after the administration of DEX in a TBI rat model. The B-cell receptor signaling pathway and the cell cycle pathway might be involved in the neuroprotective effect of DEX against TBI, Lyn and Cdk1 might be hub genes.

Enhanced oral bioavailability and neuroprotective effect of fisetin through its SNEDDS against rotenone-induced Parkinson's disease rat model

Fisetin (FS) was reported to have various pharmacological activities. But due to its lower aqueous solubility and oral bioavailability, it is not in much use. As solubility and bioavailability plays and important role in the pharmacological activity, in this research work we tried to improve the oral bioavailability of fisetin. In this research work, we developed self-nanoemulsifying drug delivery system (SNEDDS) of fisetin. Developed SNEDDS were subjected for pharmacokinetic and pharmacodynamics studies against rotenone-induced Parkinson's disease (PD) model in rats. Higher Cmax and area under the curve during pharmacokinetic study indicated that SNEDDS improved the oral bioavailability of FS and also increased the mean residence time of drug in plasma. Results of behavior parameters (locomotor, muscle co-ordination and catalepsy), biochemical estimation (TBARS, nitrite, GSH, SOD and CAT) and ELISA (soluble alfa synuclein, BDNF, TNF-α and IL-6) confirmed the significantly improved (p < 0.05) neuroprotection in rats treated with FS loaded SNEDDS as compared to rats treated with naïve FS. This study suggests that SNEDDS improved the oral bioavailability of FS which further helped in improving its neuroprotective activity in rat model of PD. It further suggests the potential use of FS-SNEDDS in effective management of PD condition.

Ceftriaxone pretreatment confers neuroprotection in rats with acute glaucoma and reduces the score of seizures induced by pentylenotetrazole in mice.

β-Lactam antibiotics such as ceftriaxone, are potent stimulators of the expression of l-glutamate transporter GLT-1 and may exert neuroprotective effects when chronically used in rats and mice. In this study, we used two animal models to test the neurological effect of subchronic treatment with ceftriaxone: experimental acute glaucoma in Wistar rats and induction of acute seizures with pentylenetetrazole in mice. We also assessed the performance of mice in the rotarod to calculate therapeutic indexes and exploratory activity in the open field. Our results showed that subchronic use of ceftriaxone was neuroprotective in both models, reducing injury in acute ischemia and ischemia/reperfusion in specific layers of retina and leading to a decrease in the seizure severity score. In behavioral experiments, we observed that ceftriaxone increased hyperactivity followed by a decrease in exploratory behavior in the open field, and there was no motor impairment in the rotarod test. We conclude that ceftriaxone may be useful as a tool in the development of new neuroprotective drugs targeting diseases which present a possible dysfunction in the balance of glutamatergic neurotransmission.

Neuroprotection by trans-resveratrol against collagenase-induced neurological and neurobehavioural deficits in rats involves adenosine A1 receptors

ABSTRACTObjective: Trans-resveratrol has been shown to have neuroprotective effects and could be a promising therapeutic agent in the treatment of intracerebral haemorrhage (ICH). This study aimed to investigate the involvement of the adenosine A1 receptor (A1R) in trans-resveratrol-induced neuroprotection in rats with collagenase-induced ICH.Methods: Sixty male Sprague–Dawley rats weighing 330–380 g were randomly divided into five groups (n = 12): (i) control, (ii) sham-operated rats, (iii) ICH rats pretreated with vehicle (0.1% DMSO saline, i.c.v.), (iv) ICH rats pretreated with trans-resveratrol (0.9 µg, i.c.v.) and (v) ICH rats pretreated with trans-resveratrol (0.9 µg) and the A1R antagonist, DPCPX (2.5 µg, i.c.v.). Thirty minutes after pretreatment, ICH was induced by intrastriatal injection of collagenase (0.04 U). Forty-eight hours after ICH, the rats were assessed using a variety of neurobehavioural tests. Subsequently, rats were sacrificed and brains were subjected to gross morphological examination of the haematoma area and histological examination of the damaged area.Results: Severe neurobehavioural deficits and haematoma with diffuse oedema were observed after intrastriatal collagenase injection. Pretreatment with trans-resveratrol partially restored general locomotor activity, muscle strength and coordination, which was accompanied with reduction of haematoma volume by 73.22% (P < 0.05) and damaged area by 60.77% (P < 0.05) in comparison to the vehicle-pretreated ICH group. The trans-resveratrol-induced improvement in neurobehavioural outcomes and morphological features of brain tissues was inhibited by DPCPX pretreatment.Conclusion: This study demonstrates that the A1R activation is possibly the mechanism underlying the trans-resveratrol-induced neurological and neurobehavioural protection in rats with ICH.

The Effect of Exosomes Derived from Bone Marrow Stem Cells in Combination with Rosuvastatin on Functional Recovery and Neuroprotection in Rats After Ischemic Stroke.

Rosuvastatin, known as a cholesterol-lowering agent, has been used as an alternative therapy after the onset of stroke. In this study, neuroprotection and functional recovery of exosomes in combination with rosuvastatin have been investigated. Sixty adult male Wistar rats were subjected to middle cerebral artery occlusion (MCAO). Exosome at the dose of 100μg and/or rosuvastatin at the dose of 20mg/kg/day for 7days were administered to rats as a therapeutic strategy. The elevated body swing test (EBST) and Garcia score were conducted as behavioral tests for the measurement of functional recovery. The histopathological and immunohistochemical analyses were also performed for the assessment of infarcted volume and neuroprotection in the brain of rats. The real-time PCR method was carried out to determine the relative expressions of the NLRP-3 and NLRP1 genes. After 7days of treatment with exosome and rosuvastatin in rats which underwent MCAO, the decrease in infarct volume of the animals treated with exosome was more pronounced compared with those treated only with exosome. The combination therapy remarkably lowered the size of infarct volume. Our observation was confirmed by the downregulation of the NLRP1 and NLRP3 genes in response to combinatory treatment of rats induced by MCOA, denoting a lower rate of cell death. The number of GFAP-positive cells were reduced in the exosome-treated group compared with the MCAO group. The rate of lipid peroxidation was measured by malondialdehyde (MDA) levels which demonstrated a significant reduction of MDA in the exosome- and rotuvastatin-treated groups when compared with the MCAO group. However, the levels of the SOD enzyme did not significantly alter when the treatment groups were compared with the MCAO group. According to our findings, it seems that the use of exosomes and rosuvastatin, as a novel treatment regimen, might promote neurological recovery after the onset of stroke.