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Objective(s): Due to the crucial role of polyamines during fetal growth and development, we aimed to determine the effect of prenatal administration of agmatine, an endogenous active metabolite of arginine, and a nutritional supplement, on autistic-like behaviors, oxidative-anti-oxidative profile, and histopathological changes of the prefrontal cortex (PFC) and CA1 area of the hippocampus in valproic acid (VPA) model of autism in male rats. Materials and Methods: VPA was injected intraperitoneally on embryonic days (ED) 12.5, and the pregnant rats were gavaged with agmatine between E6.5 to E18.5 (13 days), at doses of 0.001, 0.01, and 0.1 mg/kg. The autism-like behaviors and memory of male pups were analyzed via open-field, three-chamber, and novel object recognition tests. Serum oxidative stress and the histological changes in the PFC and CA1 were assessed at the end of the study. Results: The results suggest that prenatal agmatine reduced autistic-like behaviors by decreasing cell loss in CA1 and PFC. We observed no alterations in superoxide dismutase (SOD) level and total anti-oxidant capacity (TAC) between groups. VPA decreased catalase (CAT) activities, while agmatine decreased malondialdehyde (MDA) activity. Conclusion: Overall, this investigation suggests that agmatine may be a potential candidate for the early treatment and even prevention of appearance of autism symptoms.

Abstract Background Studies have confirmed the salutary effects of progesterone (P4) on traumatic brain injury (TBI). This study investigated the beneficial effects of P4 via its receptors on TBI, and also whether progesterone receptors (PRs) can modulate TBI through PI3K/Akt pathway. Material and methods Marmarou method was utilized to induce diffuse TBI in ovariectomized rats. P4 (1.7 mg/kg) or the vehicle (oil) was administered 30 min after TBI induction. Moreover, RU486 (PR antagonist) and its vehicle (DMSO) were injected before TBI induction and P4 injection. Brain Evans blue content, brain water content (WC), various oxidative stress parameters, IL‐1β levels, tumor necrosis factor‐α (TNF‐α), histopathological alterations, and also phosphorylated Akt (p‐Akt) and PI3K expressions in the brain were assessed 24 h after TBI. The veterinary comma scale (VCS) was measured before and after TBI at different times. Results The findings revealed that P4 caused an increase in VCS and a decrease in brain WC, oxidative stress, TNF‐α and IL‐1β levels. RU486 inhibited the beneficial effects of P4 on these indices. Moreover, RU486 prevented the reduction of brain edema, inflammation, and apoptosis caused by P4. Moreover, P4 following TBI increased the expression of PI3K/p‐Akt protein in the brain. RU486 eliminated the effects of P4 on PI3K/p‐Akt expression. Conclusion According to these findings, PRs are acting as critical mediators for the neuroprotective properties of P4 on oxidative stress, pro‐inflammatory cytokine levels, and neurological outcomes. PRs also play an important role in regulating the PI3K/p‐Akt expression and nongenomic function of P4.

Abstract Traumatic brain injury (TBI) causes progressive dysfunction that induces biochemical and metabolic changes that lead to cell death. Nevertheless, there is no definitive FDA-approved therapy for TBI treatment. Our previous immunohistochemical results indicated that the cost-effective natural Iranian medicine, Satureja khuzistanica Jamzad essential oil (SKEO), which consists of 94.16% carvacrol (CAR), has beneficial effects such as reducing neuronal death and inflammatory markers, as well as activating astrocytes and improving neurological outcomes. However, the molecular mechanisms of these neuroprotective effects have not yet been elucidated. This study investigated the possible mechanisms involved in the anti-inflammatory and anti-apoptotic properties of SKEO and CAR after TBI induction. Eighty-four male Wistar rats were randomly divided into six groups: Sham, TBI, TBI + Vehicle, TBI + CAR (100 and 200 mg/kg), and TBI + SKEO (200 mg/kg) groups. After establishing the “Marmarou” weight drop model, diffuse TBI was induced in the rat brain. Thirty minutes after TBI induction, SKEO & CAR were intraperitoneally injected. One day after TBI, injured rats exhibited significant brain edema, neurobehavioral dysfunctions, and neuronal apoptosis. Western blot results revealed upregulation of the levels of cleaved caspase-3, NFκB p65, and Bax/Bcl-2 ratio, which was attenuated by CAR and SKEO (200 mg/kg). Furthermore, the ELISA results showed that CAR treatment markedly prevents the overproduction of the brain pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6. Moreover, the neuron-specific enolase (NSE) immunohistochemistry results revealed the protective effect of CAR and SKEO on post-TBI neuronal death. The current study revealed that the possible neuroprotective mechanisms of SKEO and CAR might be related to (at least in part) modulating NF-κB regulated inflammation and caspase-3 protein expression. It also suggested that CAR exerts more potent protective effects than SKEO against TBI. Nevertheless, the administration of SKEO and CAR may express a novel therapeutic approach to ameliorate TBI-related secondary phase neuropathological outcomes.

Background: In our previous studies, the effect of sex hormones on brain edema reduction after traumatic brain injury (TBI) was demonstrated. In the current study, alone and combined effects of 17-β estradiol (E2) and vitamin D (Vit D) on TBI in male rats were investigated. Methods: Male rats were divided into six groups, including sham, TBI, vehicle, E2, Vit D, and E2+Vit D. In all groups except sham, moderate-intensity diffuse TBI was induced by the Marmarou’s method. Vehicle, E2, Vit D and their combination were intramusculary injected one and 12 hours after the TBI. The brain water content, permeability of blood brain barrier (BBB) and histopathological outcome were assessed 24h after TBI. The neurological outcome score was determined using the veterinary coma scale (VCS). Results: Significant reductions in brain water content (P

Objective: In spite of the great advances in the field of traumatic brain injury (TBI), it still remains as a global health problem. Phlebotomy has been mentioned as an effective treatment for TBI in Persian medicine. This study aimed to evaluate the possible effect of saphenous vein phlebotomy (SVP) on the alleviation of neuroinflammation and oxidative stress after TBI. Methods: Seventy-two adult male Wistar rats were randomly divided into three main groups: sham, TBI and TBI + SVP group. Animal model of TBI was made through a controlled cortical impactor (CCI) device and SVP treatment was applied 10 min after TBI. Then, neurological function, body temperature, cerebral edema, blood–brain barrier integrity, brain apoptosis, oxidative stress, and inflammation were assessed. Results: Our results indicated that SVP was associated with improvement of neurological scores 24 h post-TBI. In addition, SVP application significantly alleviated proinflammatory cytokines (IL- 1β, IL-17, and TNF-α) and oxidative stress factors as shown by reduction of malondialdehyde (MDA) and elevation of superoxide dismutase (SOD) with no significant effect on glutathione peroxidase (GPx) and nitric oxide (NO) in the brain 6 h after TBI. Besides, it reduced body temperature, attenuated severity of brain edema, and also reduced caspase-3 and number of apoptotic neurons. Conclusion: This study showed that SVP could ameliorate the severity of acute TBI, partly through alleviation of neuroinflammation, oxidative stress, and apoptosis. Further studies are necessary for more understanding the involved mechanism(s).

Objective(s): Along with increased intracranial pressure (ICP) and brain damage, brain edema is the most common cause of death in patients with hepatic encephalopathy. Curcumin can pass the blood-brain barrier and possesses anti-inflammatory and antioxidant properties. This study focuses on the curcumin protective effect on intrahepatic and extrahepatic damage in the brain. Materials and Methods: One hundred and forty-four male Albino N-Mary rats were randomly divided into 2 main groups: intrahepatic injury group and extrahepatic cholestasis group. In intra-hepatic injury group intrahepatic damage was induced by intraperitoneal (IP) injection of acetaminophen (500 mg/kg) [19] and included four subgroups: 1. Sham, 2. Acetaminophen (APAP), 3. Normal saline (Veh) which was used as curcumin solvent, and 4. Curcumin (CMN). In extrahepatic cholestasis group intrahepatic damage was caused by common bile duct litigation (BDL) and included four subgroups: 1. Sham, 2. BDL, 3. Vehicle (Veh), and 4. Curcumin (CMN). In both groups, 72 hr after induction of cholestasis, brain water content, blood-brain barrier permeability, serum ammonia, and histopathological indicators were examined and ICP was measured every 24 hr for three days.Results: The results showed that curcumin reduced brain edema, ICP, serum ammonia, and blood-brain barrier permeability after extrahepatic and intrahepatic damage. The maximum effect of curcumin on ICP was observed 72 hr after the injection.Conclusion: According to our findings, it seems that curcumin is an effective therapeutic intervention for treating encephalopathy caused by extrahepatic and intrahepatic damage.

Objective(s): The contribution of classic progesterone receptors (PR) in interceding the neuroprotective efficacy of progesterone (P4) on the prevention of brain edema and long-time behavioral disturbances was assessed in traumatic brain injury (TBI). Materials and Methods: Female Wistar rats were ovariectomized and apportioned into 6 groups: sham, TBI, oil, P4, vehicle, and RU486. P4 or oil was injected following TBI. The antagonist of PR (RU486) or DMSO was administered before TBI. The brain edema and destruction of the blood-brain barrier (BBB) were determined. Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and beam walk (BW) task were evaluated previously and at various times post-trauma. Long-time locomotor and cognitive consequences were measured one day before and on days 3, 7, 14, and 21 after the trauma. Results: RU486 eliminated the inhibitory effects of P4 on brain edema and BBB leakage (p

Since the edifice of conventional medicine is built on the pillars of past achievements, review or re-investigate the old medical manuscripts may lead to significant achievements. Avicenna was a famous Persian medieval physician and one of the pioneers of neuroscience. The aim of this study is to evaluate Avicenna's approach to traumatic brain injury (TBI), based on his main book on medicine, “Canon of Medicine”. Avicenna divided the TBI treatments into three categories: topical therapies, oral therapies, such as diets and medications, and manipulation therapies including phlebotomy, enema, foot bath, cupping, and massage. Although some of these recommendations are supported by current knowledge, many of them are still unknown and need scientific investigation to expand our knowledge of TBI treatments in the medieval period.

Protective effects of estrogen (E2) on traumatic brain injury (TBI) have been determined. In this study, the hepatoprotective effects of E2 after TBI through its receptors and oxidative stress regulation have been evaluated. Diffuse TBI induced by the Marmarou method in male rats. G15, PHTPP, MPP, and ICI182–780 as selective antagonists of E2 were injected before TBI. The results indicated that TBI induces a significant increase in liver enzymes [Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Glutamyl transferase (GGT)], and oxidants levels [Malondialdehyde (MDA), Nitric oxide (NO)] and decreases in antioxidant biomarkers [Glutathione peroxidase (GPx) and Superoxide dismutase (SOD)] in the brain and liver, and plasma. We also found that E2 significantly preserved levels of these biomarkers and enzymatic activity. All antagonists inhibited the effects of E2 on increasing SOD and GPx. Also, the effects of E2 on brain MDA levels were inhibited by all antagonists, but in the liver, only ICI + G15 + E2 + TBI group was affected. The impacts of E2 on brain and liver and plasma NO levels were inhibited by all antagonists. The current findings demonstrated that E2 probably improved liver injury after TBI by modulating oxidative stress. Also, both classic (ERβ, ERα) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are affected in the protective effects of E2.

Background and Aim: Endogenous opioids and addictive opiate drugs change many body functions. . Previous studies have referred to the effects of morphine on smooth and pulmonary muscles ., but the effects of opioids on skeletal muscles is not known well. Thus, the current study aimed at assessing the effect of a single dose of morphine on muscle fatigue in male rats. Materials and Methods: In this experimental study, 40 male Wistar rats weighing 220-270 g were randomly divided into four equal groups: control (the mice were kept in their cages and received food and water), morphine receiving group, fatigue group (the mice in this group were kept running on a treadmill . for120 minutes at a rate of 20 meters per minute), and morphine plus fatigue group. At the end of the experiments, blood samples were obtained from the corner of their eyes and were sent to the laboratory for measurement of muscle fatigue indexes including lactate dehydrogenase (LDH) and creatine phosphokinase (CPK). Results: Administration of morphine to the fatigue group decreased running time compared with the control group (P=0.009). Furthermore, administration of morphine to the fatigue group significantly increased serum levels of LDH (P=0.009) and CPK (P=0.008). Conclusion: The present study showed that administration of a single dose of morphine in rats increases muscle fatigue biomarkers (LDH, CPK).