Nobiletin prevents amyloid ß1-40-induced cognitive impairment via inhibition of neuroinflammation and oxidative/nitrosative stress.

Alzheimer's disease (AD) is presented as an age-related neurodegenerative disease with multiple cognitive deficits and amyloid ß (Aß) accumulation is the most important involved factor in its development. Nobiletin is a bioflavonoid isolated from citrus fruits peels with anti-inflammatory and anti-oxidative activity as well as anti-dementia property that has shown potency to ameliorate intracellular and extracellular Ab. The aim of the present study was to assess protective effect of nobiletin against Aß1-40-induced cognitive impairment as a consistent model of AD. After bilateral intrahippocampal (CA1 subfield) injection of Aß1-40, rats were treated with nobiletin (10 mg/kg/day; p.o.) from stereotaxic surgery day (day 0) till day + 7. Cognition function was evaluated in a battery of behavioral tasks at week 3 with final assessment of hippocampal oxidative stress and inflammation besides Nissl staining and 3-nitrotyrosine (3-NT) immunohistochemistry. Analysis of behavioral data showed notable and significant improvement of alternation in Y maze test, discrimination ratio in novel object recognition task, and step through latency in passive avoidance test in nobiletin-treated Aß group. Additionally, nobiletin treatment was associated with lower hippocampal levels of MDA and ROS and partial reversal of SOD activity and also improvement of Nrf2 with no significant effect on GSH and catalase. Furthermore, nobiletin attenuated hippocampal neuroinflammation in Aß group as shown by lower tissue levels of TLR4, NF-kB, and TNFa. Histochemical findings showed that nobiletin prevents CA1 neuronal loss in Nissl staining in addition to its alleviation of 3-nitrotyrosine (3-NT) immunoreactivity as a marker of nitrosative stress. Collectively, these findings indicated neuroprotective and anti-dementia potential of nobiletin that is partly attributed to its anti-oxidative, anti-nitrosative, and anti-inflammatory property associated with proper modulation of TLR4/NF-kB/Nrf2 pathways.

Paeonol Ameliorates Cuprizone-Induced Hippocampal Demyelination and Cognitive Deficits through Inhibition of Oxidative and Inflammatory Events.

Multiple sclerosis (MS) is a chronic and inflammatory disorder of the central nervous system with autoimmune nature that is typified by varying degrees of demyelination and axonal damage. Paeonol is an active ingredient in some medicinal plants with anti-inflammatory and neuroprotective property. This study was conducted to reveal whether paeonol can alleviate hippocampal demyelination and cognitive deficits in cuprizone-induced murine model of demyelination as a model of MS. C57BL/6 mice received oral cuprizone (400 mg/kg) for 6 weeks, and paeonol was administered p.o. at two doses of 25 or 100 mg/kg, starting from the second week post-cuprizone for 5 weeks. After assessment of learning and memory in different tasks, oxidative stress and inflammation were evaluated besides immunohistochemical assessment of hippocampal myelin basic protein (MBP). Paeonol (100 mg/kg) properly ameliorated cognitive deficits in Y maze, novel object discrimination (NOD) test, and Barnes maze with no significant improvement of performance in passive avoidance task. In addition, paeonol treatment at the higher dose was also associated with partial restoration of hippocampal level of oxidative stress and inflammatory markers including MDA, ROS, GSH, SOD, catalase, NF-kB, and TNF. Besides, paeonol improved MMP as an index of mitochondrial integrity and health and reduced MPO as a factor of neutrophil infiltration. Furthermore, paeonol treatment prevented hippocampal MBP immunoreactivity, indicating its prevention of demyelination. In conclusion, the current study showed the preventive effect of paeonol against cuprizone-induced demyelination and cognitive deficits through reversing most oxidative stress- and inflammation-related parameters in addition to its improvement of mitochondrial health.

Paeonol Ameliorates Cognitive Deficits in Streptozotocin Murine Model of Sporadic Alzheimer's Disease via Attenuation of Oxidative Stress, Inflammation, and Mitochondrial Dysfunction.

Intracerebroventricular (ICV) microinjection of diabetogenic drug streptozotocin (STZ) in rodents consistently produces a model of sporadic Alzheimer's disease (sAD) which is characterized by tau pathology and concomitant cognitive decline, insulin resistance, neuroinflammation, oxidative stress, and mitochondrial malfunction. Paeonol is an active phenolic component in some medicinal plants like Cortex Moutan with neuroprotective efficacy via exerting anti-inflammatory and anti-oxidative effects. This study was conducted to assess beneficial effect of paeonol in amelioration of cognitive deficits in ICV STZ rat model of sAD. STZ (3 mg/kg) was microinjected into the lateral ventricles on days 0 and 2, and paeonol was given p.o. at two doses of 25 (low) or 100 (high) mg/kg from day 0 (post-surgery) till day 24 post-STZ. Cognitive performance was evaluated in different tasks, and oxidative stress- and inflammation-related parameters were measured in addition to immunohistochemical assessment of glial fibrillary acidic protein (GFAP) as a marker of astrocytes. Paeonol at the higher dose ameliorated cognitive deficits in Barnes maze, novel object recognition (NOR) task, Y maze, and passive avoidance test. In addition, paeonol partially reversed hippocampal malondialdehyde (MDA), reactive oxygen species (ROS), total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase, glutathione reductase, tumor necrosis factor α (TNFα), interleukin 6 (IL-6), mitochondrial membrane potential (MMP), myeloperoxidase (MPO), and acetylcholinesterase (AChE) activity. Paeonol treatment was also associated with lower hippocampal immunoreactivity for GFAP. This study showed that paeonol can alleviate cognitive disturbances in ICV STZ rat model of sAD via ameliorating neuroinflammation, oxidative stress, mitochondrial dysfunction, and also through its attenuation of astrogliosis.

Sinomenine Alleviates Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis through Inhibiting NLRP3 Inflammasome.

Multiple sclerosis (MS) is known as a chronic neuroinflammatory disorder typified by an immune-mediated demyelination process with ensuing axonal damage and loss. Sinomenine is a natural alkaloid with different therapeutic benefits, including anti-inflammatory and immunosuppressive activities. In this study, possible beneficial effects of sinomenine in an MOG-induced model of MS were determined. Sinomenine was given to MOG35-55-immunized C57BL/6 mice at doses of 25 or 100 mg/kg/day after onset of MS clinical signs till day 30 post-immunization. Analyzed data showed that sinomenine reduces severity of the clinical signs and to some extent decreases tissue level of pro-inflammatory cytokines IL-1ß, IL-6, IL-18, TNFα, IL-17A, and increases level of anti-inflammatory IL-10. In addition, sinomenine successfully attenuated tissue levels of inflammasome NLRP3, ASC, and caspase 1 besides its reduction of intensity of neuroinflammation, demyelination, and axonal damage and loss in lumbar spinal cord specimens. Furthermore, immunoreactivity for MBP decreased and increased for GFAP and Iba1 after MOG-immunization, which was in part reversed upon sinomenine administration. Overall, sinomenine decreases EAE severity, which is attributed to its alleviation of microglial and astrocytic mobilization, demyelination, and axonal damage along with its suppression of neuroinflammation, and its beneficial effect is also associated with its inhibitory effects on inflammasome and pyroptotic pathways; this may be of potential benefit for the primary progressive phenotype of MS.

Diosgenin Attenuates Cognitive Impairment in Streptozotocin-Induced Diabetic Rats: Underlying Mechanisms.

OBJECTIVE: Prolonged diabetes mellitus causes impairments of cognition and attentional dysfunctions. Diosgenin belongs to a group of steroidal saponins with reported anti-diabetic and numerous protective properties. This research aimed to assess the effect of diosgenin on beneficially ameliorating learning and memory decline in a rat model of type 1 diabetes caused by streptozotocin (STZ) and to explore its modes of action including involvement in oxidative stress and inflammation. METHODS: Rats were assigned to one of four experimental groups, comprising control, control under treatment with diosgenin, diabetic, and diabetic under treatment with diosgenin. Diosgenin was given daily p.o. (40 mg/kg) for 5 weeks. RESULTS: The administration of diosgenin to the diabetic group reduced the deficits of functional performance in behavioral tests, consisting of Y-maze, passive avoidance, radial arm maze, and novel object discrimination tasks (recognitive). Furthermore, diosgenin treatment attenuated hippocampal acetylcholinesterase activity and malon-dialdehyde, along with improvement of antioxidants such as superoxide dismutase and glutathione. Meanwhile, the hippocampal levels of inflammatory indicators, namely interleukin 6, nuclear factor-κB, toll-like receptor 4, tumor necrosis factor α, and astrocyte-specific biomarker glial fibrillary acidic protein, were lower and, on the other hand, tissue levels of nuclear factor (erythroid-derived 2)-related factor 2 were elevated upon diosgenin administration. Besides, the mushroom-like spines of the pyramidal neurons of the hippocampal CA1 area decreased in the diabetic group, and this was alleviated following diosgenin medication. CONCLUSIONS: Taken together, diosgenin is capable of ameliorating cognitive deficits in STZ-diabetic animals, partly due to its amelioration of oxidative stress, inflammation, astrogliosis, and possibly improvement of cholinergic function in addition to its neuroprotective potential.

Ellagic acid ameliorates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis: Involvement of NLRP3 and pyroptosis.

Multiple sclerosis (MS) is presented as the most common autoimmune and demyelinating neurological disorder with incapacitating complications and with no definite therapy. Most treatments for MS mainly focus on attenuation of its severity and recurrence. To model MS reliably to study pathogenesis and efficacy of possible chemicals, experimental autoimmune encephalomyelitis (EAE) condition is induced in rodents. Ellagic acid is a neuroprotective polyphenol that can protect against demyelination. This study was planned and conducted to assess its possible beneficial effect in MOG-induced EAE model of MS with emphasis on uncovering its modes of action. Ellagic acid was given p.o. (at doses of 10 or 50 mg/kg/day) after development of clinical signs of MS to C57BL/6 mice immunized with MOG35-55. Results showed that ellagic acid can ameliorate severity of the disease and partially restore tissue level of TNFα, IL-6, IL-17A and IL-10. Besides, ellagic acid lowered tissue levels of NLRP3 and caspase 1 in addition to its mitigation of neuroinflammation, demyelination and axonal damage in spinal cord specimens of EAE group. As well, ellagic acid treatment prevented reduction of MBP and decreased GFAP and Iba1 immunoreactivity. Taken together, ellagic acid can decrease severity of EAE via amelioration of astrogliosis, astrocyte activation, demyelination, neuroinflammation and axonal damage that is partly related to its effects on NLRP3 inflammasome and pyroptotic pathway.

Berberine ameliorates lipopolysaccharide-induced learning and memory deficit in the rat: insights into underlying molecular mechanisms.

Systemic lipopolysaccharide (LPS) triggers neuroinflammation with consequent development of behavioral and cognitive deficits. Neuroinflammation plays a crucial role in the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD). Berberine is an isoquinoline alkaloid in Berberis genus with antioxidant and anti-inflammatory property and protective effects in neurodegenerative disorders. In this research, beneficial effect of this alkaloid against LPS-induced cognitive decline was assessed in the adult male rats. LPS was intraperitoneally administered at a dose of 1 mg/kg to induce neuroinflammation and berberine was given via gavage at doses of 10 or 50 mg/kg, one h after LPS, for 7 days. Treatment of LPS group with berberine at a dose of 50 mg/kg (but not at a dose of 10 mg/kg) improved spatial recognition memory in Y maze, performance in novel object recognition task (NORT), and prevented learning and memory dysfunction in passive avoidance tasks. Furthermore, berberine lowered hippocampal activity of acetylcholinesterase (AChE), malondialdehyde (MDA), protein carbonyl, activity of caspase 3, and DNA fragmentation and improved antioxidant capacity through enhancing glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, and glutathione (GSH). Besides, berberine attenuated inflammation-related indices, as was evident by lower levels of nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR4), tumor necrosis factor α (TNFα), and interleukin 6 (IL-6). Berberine also appropriately restored hippocampal 3-nitrotyrosine (3-NT), cyclooxygenase 2 (Cox 2), glial fibrillary acidic protein (GFAP), sirtuin 1, and mitogen-activated protein kinase (p38 MAPK) with no significant alteration of brain-derived neurotrophic factor (BDNF). In summary, berberine could partially ameliorate LPS-induced cognitive deficits via partial suppression of apoptotic cascade, neuroinflammation, oxido-nitrosative stress, AChE, MAPK, and restoration of sirtuin 1.

Ellagic acid ameliorates learning and memory deficits in a rat model of Alzheimer's disease: an exploration of underlying mechanisms.

RATIONALE: Alzheimer's disease (AD) is a neurodegenerative disorder with irreversible loss of intellectual abilities. Current therapies for AD are still insufficient. OBJECTIVE: In this study, the effect of ellagic acid on learning and memory deficits was evaluated in intrahippocampal amyloid beta (Aß25-35)-microinjected rats and its modes of action were also explored. METHODS: AD rat model was induced by bilateral intrahippocampal microinjection of Aß25-35 and ellagic acid was daily administered (10, 50, and 100 mg/kg), and learning, recognition memory, and spatial memory were evaluated in addition to histochemical assessment, oxidative stress, cholinesterases activity, and level of nuclear factor-kappaB (NF-κB), Toll-like receptor 4 (TLR4), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). RESULTS: The amyloid beta-microinjected rats showed a lower discrimination ratio in novel object and alternation score in Y maze tasks and exhibited an impairment of retention and recall capability in passive avoidance paradigm and higher working and reference memory errors in radial arm maze (RAM). In addition, amyloid beta group showed a lower number of Nissl-stained neurons in CA1 area in addition to enhanced oxidative stress, higher activity of cholinesterases, greater level of NF-κB and TLR4, and lower level of nuclear/cytoplasmic ratio for Nrf2 and ellagic acid at a dose of 100 mg/kg significantly prevented most of these abnormal alterations. CONCLUSIONS: Ellagic acid pretreatment of intrahippocampal amyloid beta-microinjected rats could dose-dependently improve learning and memory deficits via neuronal protection and at molecular level through mitigation of oxidative stress and acetylcholinesterase (AChE) activity and modulation of NF-κB/Nrf2/TLR4 signaling pathway.

Antidepressant and anxiolytic activity of Lavandula officinalis aerial parts hydroalcoholic extract in scopolamine-treated rats.

CONTEXT: Anxiety and depression are common in Alzheimer's disease (AD). Despite some evidence, it is difficult to confirm Lavandula officinalis Chaix ex Vill (Lamiaceae) as an anxiolytic and antidepressant drug. OBJECTIVE: The effects of L. officinalis extract were studied in scopolamine-induced memory impairment, anxiety and depression-like behaviour. MATERIALS AND METHODS: Male NMRI rats were divided into control, scopolamine alone-treated group received scopolamine (0.1 mg/kg) intraperitoneally (i.p.), daily and 30 min prior to performing behavioural testing on test day, for 12 continuous days and extract pretreated groups received aerial parts hydro alcoholic extract (i.p.) (100, 200 and 400 mg/kg), 30 min before each scopolamine injection. Memory impairment was assessed by Y-maze task, while, elevated plus maze and forced swimming test were used to measure anxiolytic and antidepressive-like activity. RESULTS: Spontaneous alternation percentage in Y maze is reduced by scopolamine (36.42 ± 2.60) (p ≤ 0.001), whereas lavender (200 and 400 mg/kg) enhanced it (83.12 ± 5.20 and 95 ± 11.08, respectively) (p ≤ 0.05). Also, lavender pretreatment in 200 and 400 mg/kg enhanced time spent on the open arms (15.4 ± 3.37 and 32.1 ± 3.46, respectively) (p ≤ 0.001). On the contrary, while immobility time was enhanced by scopolamine (296 ± 4.70), 100, 200 and 400 mg/kg lavender reduced it (193.88 ± 22.42, 73.3 ± 8.25 and 35.2 ± 4.22, respectively) in a dose-dependent manner (p ≤ 0.001). DISCUSSION AND CONCLUSION: Lavender extracts improved scopolamine-induced memory impairment and also reduced anxiety and depression-like behaviour in a dose-dependent manner.

Acetyl-l-carnitine protects dopaminergic nigrostriatal pathway in 6-hydroxydopamine-induced model of Parkinson's disease in the rat.

Parkinson's disease (PD) is a movement disorder and the second most common neurodegenerative disease worldwide in which nigrostriatal dopaminergic neurons within substantia nigra pars compacta (SNC) are lost, with clinical motor and non-motor symptoms including bradykinesia, resting tremor, rigidity, stooping posture and cognitive deficits. This study was undertaken to evaluate the neuroprotective potential of acetyl-l-carnitine (ALC) against unilateral striatal 6-hydroxydopamine (6-OHDA)-induced model of PD and to explore some involved mechanisms. In this experimental study, intrastriatal 6-OHDA-lesioned rats received ALC at doses of 100 or 200mg/kg/day for 1 week. ALC (200mg/kg) lowered apomorphine-induced rotational asymmetry and reduced the latency to initiate and the total time in the narrow beam test, reduced striatal malondialdehyde (MDA), increased catalase activity and glutathione (GSH) level, prevented reduction of nigral tyrosine hydroxylase (TH)-positive neurons and striatal TH-immunoreactivity, and lowered striatal glial fibrillary acidic protein (GFAP) and its immunoreactivity as an indicator of astrogliosis, and nuclear factor NF-kappa B and Toll-like receptor 4 (TLR4) as reliable markers of neuroinflammation. Meanwhile, ALC at both doses mitigated nigral DNA fragmentation as a valuable marker of apoptosis. The results of this study clearly suggest the neuroprotective effect of ALC in 6-OHDA-induced model of PD through abrogation of neuroinflammation, apoptosis, astrogliosis, and oxidative stress and it may be put forward as an ancillary therapeutic candidate for controlling PD.