Neuroprotective effect of alpha-pinene is mediated by suppression of the TNF-α/NF-κB pathway in Alzheimer's disease rat model.

Monoterpene alpha-pinene possesses antioxidant, cardioprotective, and neuroprotective properties. We evaluated the effect of alpha-pinene on oxidative/nitrosative stress, neuroinflammation, and molecular and behavioral changes induced by beta-amyloid (Aß)1-42 in rats and investigated the possible mechanisms of these outcomes. Male Wistar rats received alpha-pinene (50 mg/kg intraperitoneally) for 14 consecutive days after intrahippocampal injection of Aß1-42 . Alpha-pinene decreased malondialdehyde and nitric oxide levels, increased glutathione content, and enhanced catalase activity in Aß-injected rats. Also, messenger RNA expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, nuclear factor κB, and N-methyl- d-aspartate receptor subunits 2A and 2B reduced in the hippocampus of these animals. Besides this, alpha-pinene repressed the Aß1-42 -induced reduction of nicotinic acetylcholine receptor α7 subunit and brain-derived neurotrophic factor expression. Treatment with alpha-pinene caused Aß-receiving rats to spend more time in the target quadrant in the Morris water maze test and led to an increase in percentages of open arm entrance and time spent in the open arm in the elevated plus-maze test. We concluded that alpha-pinene strengthens the antioxidant system and prevents neuroinflammation in the hippocampus of rats receiving Aß. It improves spatial learning and memory and reduces anxiety-like behavior in these animals. Consequently, alpha-pinene alleviates Aß-induced oxidative/nitrosative stress, neuroinflammation, and behavioral deficits. It is probably a suitable candidate for the treatment of neurodegenerative diseases.

Alpha-pinene alleviates CCl4-induced renal and testicular injury in rats by targeting oxidative stress, inflammation, and apoptosis.

Objectives: Renal and testicular disorders are primarily associated with oxidative damage and inflammation. Here, alpha-pinene (a type of monoterpene) was investigated for its effect on oxidative/nitrosative stress and the expression of inflammatory and apoptotic factors in the kidneys and testes of rats treated with CCl4. Materials and Methods: CCl4 was injected intraperitoneally (IP) at a dose of 2 ml/kg (twice a week for six weeks). Alpha-pinene (50 mg/kg/day, IP) was also treated during the same period. Results: CCl4 increased the level of malondialdehyde (P<0.01 in the kidney and P<0.001 in the testis) and nitric oxide (P<0.001 in the kidney and P<0.01 in the testis) and decreased the levels of glutathione (P<0.05) in the kidneys and testicles of rats. CCl4 also reduced the catalase enzyme activity in the kidneys (P<0.05) but did not affect its activity in the testis. In addition, CCl4 enhanced the mRNA expression of TNF-α (P<0.01), nuclear factor-κB (P<0.05), and Bax (P<0.05 in the kidney and P<0.01 in the testis) and decreased the expression of Bcl-2 (P<0.05) in both organs. Alpha-pinene prevented all the mentioned changes, but it did not influence the expression of Bcl-2 in the kidneys of rats receiving CCl4. Conclusion: Alpha-pinene may have the potential to prevent renal and testicular diseases by strengthening the antioxidant system in the kidneys and testis, and inhibiting oxidative/nitrosative stress, inflammation, and apoptosis caused by CCl4.

Carvone suppresses oxidative stress and inflammation in the liver of immobilised rats.

OBJECTIVE: The investigation of the effect of carvone (a natural monoterpene) on liver damage caused by chronic immobilisation. METHODS: Male Wistar rats were divided into four groups: control, carvone, stress, and stress-carvone. To induce stress, rats were placed in a restrainer (6 h/21 day) and carvone was treated by gavage at a dose of 20 mg/kg. RESULTS: Alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase activities were significantly increased in sera of immobilised rats. Chronic immobilisation also increased malondialdehyde levels and decreased reduced glutathione content, as well as increased TNF-α, IL-1ß, IL-6, and NF-κB mRNA expression and also led to the infiltration of inflammatory cells in the liver parenchyma. Carvone's 21-day treatment prevented all of these changes in immobilised rats. CONCLUSION: It is concluded that carvone has effectively prevented chronic immobilisation-induced liver injury, most probably through its antioxidant and anti-inflammatory capabilities.

Protective effect of alpha-linoleic acid on Aß-induced oxidative stress, neuroinflammation, and memory impairment by alteration of α7 nAChR and NMDAR gene expression in the hippocampus of rats.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects many older people around the world. Numerous studies are underway to evaluate the protective effects of natural products in AD. Alpha-linoleic acid (ALA) is an essential unsaturated fatty acid that exhibits neuroprotective outcomes in rat models of ischemic stroke and Parkinson's disease. This research aimed to investigate the effect of ALA on oxidative stress, neuroinflammation, neuronal death, and memory deficit induced by amyloid-beta (Aß) peptide. After intrahippocampal injection of Aß1-42, rats received ALA (150 µg/kg, subcutaneously) for 14 consecutive days. ALA decreased the levels of malondialdehyde and nitric oxide, enhanced glutathione content, and increased the activity of catalase in the hippocampus of the rat model of AD. It also reduced the expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, nuclear factor-kappa B, and N-methyl-d-aspartate receptor subunits NR2A and NR2B mRNAs in the hippocampus, prevented the neuronal loss in the CA1 region, and enhanced the expression of α7 nicotinic acetylcholine receptor. In addition, ALA allowed Aß1-42-injected rats to spend less time and distance to reach the hidden platform in the Morris water maze test and to swim longer in the target quadrant. We concluded that ALA reduces the biochemical, molecular, histological, and behavioral changes caused by Aß1-42 and it may be an effective option for treating AD.

Morin attenuates memory deficits in a rat model of Alzheimer's disease by ameliorating oxidative stress and neuroinflammation.

This study aimed to investigate the effect of flavonoid morin on oxidative/nitrosative stress, neuroinflammation, and histological, molecular, and behavioral changes caused by amyloid-beta (Aß)1-42 in male Wistar rats (Alzheimer's disease model). Rats received morin (20 mg/kg, oral gavage) for 14 consecutive days after intrahippocampal injection of Aß1-42. Morin decreased the levels of malondialdehyde and nitric oxide, increased glutathione content, and enhanced catalase activity in the hippocampus of animals receiving Aß1-42. It also reduced the expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, nuclear factor-kappa B, and N-methyl-D-aspartate receptor subunits 2A and 2B and increased the expression of brain-derived neurotrophic factor and α7 nicotinic acetylcholine receptor in the hippocampus of Aß1-42-injected rats. Besides, morin modified neuronal loss and histological changes in the CA1 region of the hippocampus. Morin allowed Aß1-42-infused rats to swim more time in the target quadrant in the Morris water maze test. It is concluded that morin may be suitable for the prevention and treatment of Alzheimer's disease by strengthening the antioxidant system, inhibiting neuroinflammation, preventing neuronal death, and enhancing memory function.

Hepatoprotective effect of limonene against chronic immobilization induced liver damage in rats.

Prolonged immobilization may impair the physiological functions of various organs of the body, including the liver, brain, and heart. In this study, we investigated the hepatoprotective effect of limonene (a monoterpene) in male rats exposed to chronic immobilization. Rats were exposed to immobilization stress (6 h/21 days) and received limonene (10 mg/kg, oral gavage) during this period. Chronic immobilization increased the levels of liver enzymes alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase in serum. Increased levels of malondialdehyde and decreased glutathione content were also observed in the liver tissue of immobilized rats. Expression of TNF-α, IL-1ß, IL-6, and NF-κB mRNA was increased, and infiltrated cells were also observed in the liver parenchyma in rats exposed to chronic immobilization. Limonene prevented all these changes in immobilized rats. These results suggest that limonene, due to its antioxidant and anti-inflammatory effects, rescues the liver from damages caused by chronic immobilization.

Teucrium polium in prevention of steatohepatitis in rats.

BACKGROUND: In this study, we tried to evaluate whether the ethyl acetate (EtOAc) extract of Teucrium polium, with a high antioxidant activity, is able to prevent the incidence of nonalcoholic steatohepatitis. METHODS: Nonalcoholic steatohepatitis was induced in male N-Mary rats using a methionine/choline-deficient (MCD) diet. Rats were given normal diet (A), normal diet+EtOAc extract (B), MCD diet (C) and MCD diet+EtOAc (D). RESULTS: The MCD diet led to grade 1 liver steatosis, inflammation and ballooning degeneration. In group D, these factors abated to grade 0 in 80% of the rats. In groups receiving the EtOAc extract, lipoprotein profiles had significantly improved relative to those not receiving the extract. Also, a dramatic reduction was observed in the sera alkaline phosphatase, aspartate aminotransferase and alanine aminoteransferase activities. The activities of the liver superoxide dismutase, glutathione peroxidase and glutathione reductase enzymes were also enhanced. CONCLUSION: The EtOAc extract could reverse the adverse effects of the MCD diet.

Apigenin reduces human insulin fibrillation in vitro and protects SK-N-MC cells against insulin amyloids.

Deposition of proteins is a key pathogenic feature of more than 20 amyloid-related diseases. Inhibiting or reversing amyloid aggregation via the use of small molecules is proposed as two useful approaches in hampering the development of these diseases. In this research, we examined the inhibitory and disruptive effects of apigenin, a common dietary flavonoid with multiple pharmacological properties, against human insulin fibrillization. Besides, we investigated the potential cytotoxicity of insulin fibrils on SK-N-MC cells in the presence and absence of apigenin. The increase in Thioflavin T (ThT) and anilinonaphthalene-8-sulfonic acid (ANS) fluorescent intensities and Congo red absorbance were inhibited by simultaneous incubation of various concentrations of apigenin with insulin, in a dose-dependent manner. The spectroscopy results were confirmed by transmission electron microscopy, where lower extent of fibrillar structures was observed in the presence of apigenin. In addition, the cell exposure to the co-incubated insulin amyloids with apigenin led to the increased viability and decreased LDH release dose-dependently, compared to cells exposed to insulin fibrils alone. Co-incubation with apigenin also attenuated the extent of apoptotic cell death induced by insulin fibrils. It can be concluded that apigenin possess in vitro anti-amyloidogenic activities as well as protective effects against insulin amyloids cytotoxicity.

Teucrium polium reversed the MCD diet-induced liver injury in rats.

In the present study, we evaluated the ability of Teucrium polium ethyl acetate fraction, with high antioxidant activity, in the treatment of nonalcoholic steatohepatitis (NASH) in rats and its possible effect on factors involved in pathogenesis of the disease. To induce NASH, a methionine and choline deficient (MCD) diet was given to N-Mary rats for 8 weeks. After NASH development, MCD-fed rats were divided into 2 groups: NASH group that received MCD diet and NASH + T group which was fed MCD diet plus ethyl acetate fraction of T. polium orally for 3 weeks. Histopathological evaluations revealed that treatment with the extract has abated the severity of NASH among the MCD-fed rats. In addition, the fraction reduced the elevated levels of hepatic tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-ß) gene expression and also the elevated level of malondialdehyde (MDA). In addition, the extract increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and enhanced the level of hepatic glutathione (GSH). Moreover, the fraction treatments lowered caspase-3 level and the phosphorylated form of C-Jun N-terminal kinase (JNK) and augmented the phosphorylated level of extracellular regulated kinase1/2 (ERK1/2). These results indicate that the ethyl acetate fraction of T. poium effectively reversed NASH, mainly due to its strong antioxidant and anti-inflammatory properties.

Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis.

In this study, we were aimed to evaluate the probable effect of the crud extract of Silybum marianum, with high polyphenolic content, on experimental nonalcoholic steatohepatitis (NASH). To induce NASH, a methionine and choline deficient (MCD) diet was given to N-Mary rats for 8 weeks. After NASH development, MCD-fed rats were divided into two groups: MCD groups received MCD diet and MCD+S group was fed MCD diet plus crude extract of S. marianum orally for 3 weeks. Control group was fed a normal diet for 11 weeks. Finally, all rats were sacrificed. Plasma alanine amino transferase (ALT) and aspartate amino transferase (AST) levels were evaluated. In addition, the following hepatic factors were also evaluated: liver histology, malondialdehyde (MDA) and reduced glutathione (GSH) contents, gene expressions of TNF-α and TGF-ß and immunoblot evaluations of caspase-3, ERK/p-ERK, JNK/pJNK and p38/pp38. Histopathological evaluations of the liver samples revealed that treatment with the S. marianum extract has abated the severity of NASH among the MCD-fed rats. Also, a significant reduction was observed in the sera ALT and AST activities. In addition, the extract caused dramatic reduction in the elevated hepatic TNF-α and TGF-ß mRNA and MDA levels along with an increase in the GSH content. Moreover, the plant extract treatments significantly lowered activation of procaspase-3 to active caspase-3 and also lowered the phosphorylated form of JNK among the same group of rats. These results suggest that the S. marianum crude extract beneficial effects on NASH are mainly due to its antioxidant and anti-inflammatory activities.