Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Effects of Exercise and Estrogen on Anxiety-like Behaviors in ‎Ovariectomized Mice

BACKGROUND AND OBJECTIVE: Anxiety is a major symptom of menopause caused by loss of ovarian activity. Anxiety increases the intensity of vasomotor symptoms in menopausal women. This study aimed to compare the effects of exercise and estrogen on anxiety level of ovariectomized mice.&nbsp; METHODS: This empirical study was conducted on 28 mice (weight: 25-35 grams) divided into four groups of seven, including ovariectomy, ovariectomy and exercise, ovariectomy and estrogen (40 mg/kg of estradiol valerate), and ovariectomy combined with exercise and estrogen. Animals were initially ovariectomized and one week later, they were placed on treadmills to run at medium intensity for 30 minutes per day. Intervention continued for five days per week, and after four weeks, anxiety was evaluated using elevated plus-maze. FINDINGS: In this study, estrogen significantly increased the percentage of open arm entry (OAE) compared to ovariectomy group (22.13&plusmn;4.72 vs. 4.91&plusmn;3.18, respectively) (p<0.05). In addition, combination of estrogen and exercise significantly increased open arm time (OAT) compared to ovariectomy group (46.19&plusmn;6.82 vs. 4.91&plusmn;3.18, respectively) (p<0.001). However, no significant difference was observed between exercise and estrogen groups. Also, exercise alone increased OAE compared to ovariectomy group (24.54&plusmn;3.18 vs. 13.79&plusmn; 3.23, respectively) (p<0.05). Percentage of OAE in groups of estrogen, exercise and combined exercise and estrogen was 30.61&plusmn;1.25, 24.54&plusmn;3.18 and 46.08&plusmn;1.04, respectively, which was indicative of no significant difference. However, estrogen and combined estrogen and exercise significantly increased OAE compared to ovariectomy group (p<0.001). CONCLUSION: According to the results of this study, similar to estrogen, exercise could reduce the anxiety induced by ovariectomy in mice.&nbsp

The effect of intra-striatal administration of GPR55 agonist (LPI) and antagonist (ML193) on sensorimotor and motor functions in a Parkinson's disease rat model

Objective:G protein-coupled receptor 55 (GPR55) is an orphan G protein-coupled receptor with various physiological functions. Recent evidence suggests that this receptor may be involved in the control of motor functions. Therefore, in the present study, we evaluated the effects of intra-striatal administration of GPR55 selective ligands in a rat model of Parkinson's disease.Methods:Experimental Parkinson was induced by unilateral intra-striatal administration of 6-hydroxydopamine (6-OHDA, 10 μg/rat). L-α-lysophosphatidylinositol (LPI, 1 and 5 μg/rat), an endogenous GPR55 agonist, and ML193 (1 and 5 μg/rat), a selective GPR55 antagonist, were injected into the striatum of 6-OHDA-lesioned rats. Motor performance and balance skills were evaluated using the accelerating rotating rod and the ledged beam tests. The sensorimotor function of the forelimbs and locomotor activity were assessed by the adhesive removal and open field tests, respectively.Results:6-OHDA-lesioned rats had impaired behaviors in all tests. Intra-striatal administration of LPI in 6-OHDA-lesioned rats increased time on the rotarod, decreased latency to remove the label, with no significant effect on slip steps, and locomotor activity. Intra-striatal administration of ML193 also increased time on the rotarod, decreased latency to remove the label and slip steps in 6-OHDA-lesioned rats mostly at the dose of 1 μg/rat.Conclusions:This study suggests that the striatal GPR55 is involved in the control of motor functions. However, considering the similar effects of GPR55 agonist and antagonist, it may be concluded that this receptor has a modulatory role in the control of motor deficits in an experimental model of Parkinson. © 2020 Scandinavian College of Neuropsychopharmacology

Ameliorating effect of troxerutin in unilateral ureteral obstruction induced renal oxidative stress, inflammation, and apoptosis in male rats

Unilateral ureteral obstruction (UUO) induces renal injury and troxerutin attenuates the inflammatory parameters and decreases oxidative stress. Accordingly, this study explored the renoprotective effect of troxerutin in UUO-induced renal oxidative stress, inflammation, and apoptosis in male Wistar rats. Animals were randomly separated into five groups (n = 8): control, UUO, and three UUO groups treated with troxerutin (1, 10, and 100 mg/kg). UUO-induced and vehicle/troxerutin administration was continued for 3 days. Then serum creatinine, mean arterial pressure (MAP), renal perfusion pressure (RPP), renal vascular resistance (RVR), and renal blood flow (RBF) were measured. Superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase activities, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels as some oxidative stress parameters were measured in the left kidney. The immunoblotting method was applied to evaluate the cleaved caspase-3 Bax, Bcl-2, and TNF-α proteins level. The hematoxylin and eosin method was used to assess the kidney tissue damage score (KTDS). In 3 days, UUO significantly increased serum creatinine level, KTDS, RVR, MDA, Bax, cleaved caspase-3, and TNF-α protein levels (p &#x003C; 0.05); and decreased RBF, TAC, SOD, catalase, GPx activity levels and Bcl-2 protein expression level in the left kidney (p &#x003C; 0.05). Troxerutin (100 mg/kg) significantly attenuates the indicators alteration induced by UUO. Our findings represented that the renoprotective effect of troxerutin may be related to its anti-oxidative stress, anti-inflammation, anti-apoptosis, and RBF improver properties. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

The effect of Metformin on tactile learning and anxiety like-behavior in ovariectomized mice

Introduction: Estrogen regulates many processes in the brain such as synaptic formation, learning, and memory. Empirical evidence shows that there is a correlation among menopause, memory impairment, and anxiety due to Estrogen deficiency. In this study, we tested the effect of Metformin (Met) with antioxidant effect, which can improve the impairment of tactile learning and anxiety-like behavior in ovarectomized mice. Methods: Thirty-two female mice weighting 20&plusmn;5 g were randomly divided into four groups of eight, including sham group, ovariectomy, ovariectomy with doses 7 and 15 mg/kg of Met. At first, mice were ovariectomized and then they were treated with the doses of the Met or water for 21 days. Then, tactile learning (by Novel Object Recognition Test) and anxiety like-behavior (by Elevated Plus-maze) were determined. Results: Met at the doses of 7 or 15 mg/kg significantly improved tactile learning compared to the ovariectomy group. Met at the doses of 7 or 15 mg/kg significantly increased Open Arm Time (%OAT) and Open Arm Entries (%OAE) compared to the ovariectomy group. Conclusion: Met especially at the dose of 7 mg/kg showed a significant role in improving the anxiety and tactile learning in the ovariectomized mice

Effect of DSP-4 induced central noradrenergic depletion on tactile learning in rat

Objective: There is general agreement that norepinephrine could modulate neuronal responses to nonmonoaminergic synaptic inputs in the somatosensory cortex. In the present study, we investigated the effect of central norepinephrine depletion on tactile learning in rats. Methods: Central norepinephrine depletion was induced using 50 mg/kg of N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP-4) and verified by high performance liquid chromatography. Memory performance was assessed 1 and 5 weeks after DSP-4 treatment using novel object recognition test. Result: We observed a learning impairment in both DSP-4 groups, as the preference index was not significantly altered when compared to chance level (50%). Discussion: These findings suggest that depletion of central norepinephrine by DSP-4 leads to impairment of the tactile learning in rats, which can last at least for 35 days. © W. S. Maney & Son Ltd 2012

Effect of General Hypothermia on the Embolic Model of Stroke in the Male Rat

Introduction: Hypothermia has neuroprotective effects in permanent or transient models of cerebral artery occlusion. In the current study, neuroprotective effect of general hypothermia in the embolic model of stroke, in which no study has been conducted to date. Methods: In this experimental study, twenty-four male Wistar rats (250 to 350 g) were divided into three groups as following: sham, Control and hypothermia. Stroke was induced by clot injection into the right middle cerebral artery (MCA). General hypothermia was induced at 6 h after stroke. Neurological deficits were measured at 24 and 48 h after ischemia. Infarction volume and brain edema were determined at the end of study. Results: General hypothermia significantly decreased infarct volume (P<0.001) and neurological deficits (P<0.001). No significant difference was observed between hypothermia and control group in brain edema. Conclusion: According to the findings of the present study, general hypothermia at six h after ischemia shows neuroprotection in the embolic model of stroke

The Effects of the Ethanolic Extract of Vitex Agnus Castus on Stroke Outcomes in Ovariectomized Mice

BACKGROUND AND OBJECTIVE: The prevalence of stroke in premenopausal women is lower than men. In fact, estrogen is known as a potent neuroprotective agent in cerebral ischemia before menopause. Phytoestrogens are considered to be less risky than chemical estrogens. In this study, considering the phytoestrogenic properties of Vitex agnus custus, the effects of the ethanolic extract of this plant on stroke outcomes in a model of middle cerebral artery occlusion were investigated in ovariectomized mice. METHODS: In this experimental study, 32 mice, weighing 25-35 g, were randomly divided into 4 groups (8 mice per group): 1) sham group, 2) control group (ovariectomized, treated with 1 ml/kg saline for one month, followed by stroke induction), 3) Vitex group (ovariectomized, treated with 80 mg/kg of Vitex extracts in 1 mL saline every day for a month), and 4) estrogen group (ovariectomized, treated with 40 &mu;g/kg of estradiol valerate in 1 mL saline every day for a month). After one month, stroke was induced in ovariectomized mice by cauterizing the middle cerebral artery. Infarct volume and neurological disorders were evaluated one week after stroke induction. FINDINGS:&nbsp;A week after stroke induction, infarct volume in the control, estrogen, and Vitex groups was 11.98&plusmn;2.33, 3.41&plusmn;1.01, and 5&plusmn;1.10, respectively.&nbsp;Vitex extracts and estrogen could decrease infarct volume, compared to the control group (p<0.05). Also, estrogen and Vitex extracts reduced neurological deficits, compared to the control group (p<0.001). A week after stroke induction, sensorimotor disorders in the control, estrogen, and Vitex groups were 50&plusmn;7, 15&plusmn;2, and 21&plusmn;4.09, respectively. In fact, a significant difference was observed between the control and other groups (p<0.001). CONCLUSION: The findings of the present study showed that Vitex extracts, similar to estrogen, have neuroprotective effects, following middle cerebral artery occlusion in ovariectomized mice