Comparison of neuroprotective effects of a topiramate-loaded biocomposite based on mesoporous silica nanoparticles with pure topiramate against methylphenidate-induced neurodegeneration.

BACKGROUND: Methylphenidate (MPH) abuse has been criticized for its role in neurodegeneration. Also, a high risk of seizure was reported in the first month of MPH treatment. Topiramate, a broad-spectrum Antiepileptic Drug (AED), has been used as a neuroprotective agent in both aforementioned complications. Nanotechnology is introduced to increase desirable neurological treatment with minimum side effects. We aimed to investigate the potential neuroprotective activity of topiramate loaded on nanoparticles. METHODS AND RESULTS: MTT assay was performed to evaluate the cellular cytotoxicity of Mesoporous Silica Nanoparticles (MSN). Male rats were randomly divided into eight groups. Rats received an intraperitoneal (i.p) MPH (10 mg/kg) injection and a daily oral dose of topiramate (TPM, 30 mg/kg), MSN with Zn core (10 and 30 mg/kg), and MSN with Cu core (10 and 30 mg/kg) for three weeks. On day 21, a seizure was induced by a single injection of pentylenetetrazole (PTZ) to evaluate the protective effects of TPM-loaded nanoparticles on seizure latency and duration following MPH-induced neurotoxicity. Moreover, the hippocampal content of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), malondialdehyde (MDA), and the anti-oxidant enzymes (SOD, GPx, and GR) activities were assessed. Also, BAX and Bcl-2 as two main apoptotic markers were evaluated. RESULTS: MPH neurotoxicity was observed as a raised duration and reduced latency in PTZ-induced seizure. However, TPM-loaded MSN with Zn species (NE) treatment reduced the duration and improved the latency time. Also, NE and, somewhat, TPM-loaded MSN with Cu species (NM) administration reduced inflammatory cytokines, MDA, and Bax levels and increased activities in the rat hippocampus. CONCLUSION: TPM-loaded nanoparticles could be used as neuroprotective agents against MPH-induced neurodegeneration by improving seizure parameters and reducing inflammatory, oxidant, and apoptotic factors.

Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases.

Tryptophan metabolism along the kynurenine pathway is of central importance for the immune function. It prevents hyperinflammation and induces long-term immune tolerance. Accumulating evidence also demonstrates cytoprotective and immunomodulatory properties of kynurenine pathway in conditions affecting either central or peripheral nervous system as well as other conditions such as inflammatory bowel disease (IBD). Although multilevel association exists between the inflammatory bowel disease (IBD) and various neurologic (e.g., neurodegenerative) disorders, it is believed that the kynurenine pathway plays a pivotal role in the development of both IBD and neurodegenerative disorders. In this setting, there is strong evidence linking the gut-brain axis with intestinal dysfunctions including IBD which is consistent with the fact that the risk of neurodegenerative diseases is higher in IBD patients. This review aims to highlight the role of kynurenine metabolic pathway in various neurologic and psychiatric diseases as well as relationship between IBD and neurodegenerative disorders in the light of the kynurenine metabolic pathway.

Therapeutic potential of infliximab for pruritus in mice model of cholestasis induced by bile duct ligation: Possible involvement of IL-31.

BACKGROUND: Cholestatic pruritus is a distressful sensation that can cause a massive desire of scratching skin. Despite maximum medication therapy, some patients still experience pruritus. In this study, we evaluated the effect of infliximab on cholestatic pruritus induced in mice by bile duct ligation. METHODS: Twenty-four balb/c mice were randomly assigned to three groups; sham, control, and treatment. The bile duct ligation procedure was performed on mice in the control and treatment groups. After six days, mice in the treatment group received subcutaneous administration of infliximab, and the next day all mice were subjected to the scratching behavior test. Skin, dorsal root ganglia (DRG), and blood samples of mice were collected and evaluated by histopathological, molecular, and biochemical tests. RESULTS: The scratching behavior has significantly decreased in mice with cholestasis after the administration of infliximab. The levels of TNFα, TNFR1, TNFR2, NF-κB, and IL-31were higher in control mice compared to sham. In addition, expression levels of TNFR1, NF-κB, and IL-31 were decreased in the treatment group compared to the controls in skin and DRG, while TNFR2 levels were decreased only in DRG. CONCLUSION: Infliximab can block TNFα interaction with receptors and inhibit further inflammatory response. Also, our results suggested that infliximab can suppress IL-31 expression indirectly, which is a well-known cytokine in pruritus pathophysiology Infliximab can be a potential therapeutic approach in resistant pruritus in cholestatic disorders.

Orexin receptor antagonists in the pathophysiology and treatment of sleep disorders and epilepsy.

The correlation between sleep and epilepsy has been argued over the past decades among scientists. Although the similarities and contrasts between sleep and epilepsy had been considered, their intertwined nature was not revealed until the nineteenth century. Sleep is recognized as a recurring state of mind and body through alternating brain electrical activities. It is documented that sleep disorders are associated with epilepsy. The origin, suppression, and spread of seizures are affected by sleep. As such, in patients with epilepsy, sleep disorders are a frequent comorbidity. Meanwhile, orexin, a wake-promoting neuropeptide, provides a bidirectional effect on both sleep and epilepsy. Orexin and its cognate receptors, orexin receptor type 1 (OX1R) and type 2 (OX2R), orchestrate their effects by activating various downstream signaling pathways. Although orexin was considered a therapeutic target in insomnia shortly after its discovery, its potential usefulness for psychiatric disorders and epileptic seizures has been suggested in the pre-clinical studies. This review aimed to discuss whether the relationship between sleep, epilepsy, and orexin is clearly reciprocal.

A comprehensive insight into the anti-inflammatory properties of dapsone.

The 4,4'-diaminodiphenyl sulfone (DDS), also known as dapsone, is traditionally used as a potent anti-bacterial agent in clinical management of leprosy. For decades, dapsone has been among the first-line medications used in multidrug treatment of leprosy recommended by the World Health Organization (WHO). Shortly after dapsone's discovery as an antibiotic in 1937, the dual function of dapsone (anti-microbial and anti-inflammatory) was elucidated. Dapsone exerts its anti-bacterial effects by inhibiting dihydrofolic acid synthesis, leading to inhibition of bacterial growth, while its anti-inflammatory properties are triggered by inhibiting reactive oxygen species (ROS) production, reducing the effect of eosinophil peroxidase on mast cells and downregulating neutrophil-mediated inflammatory responses. Among the leading mechanisms associated with its anti-microbial/anti-protozoal effects, dapsone clearly has multiple antioxidant, anti-inflammatory, and anti-apoptotic functions. In this regard, it has been described in treating a wide variety of inflammatory and infectious skin conditions. Previous reports have explored different molecular targets for dapsone and provided insight into the anti-inflammatory mechanism of dapsone. This article reviews several basic, experimental, and clinical approaches on anti-inflammatory effect of dapsone.

Dapsone improves the vincristine-induced neuropathic nociception by modulating neuroinflammation and oxidative stress.

BACKGROUND: Peripheral neuropathy is a dose-limiting adverse effect of vincristine (VCR) in cancer chemotherapies. Dapsone is commonly used for the prevention of opportunistic infections following cancer therapies. Therefore, a high rate of VCR and dapsone co-administration has occurred in leukemias. Recently neuroprotective effects of dapsone have been reported in various diseases. OBJECTIVES: Regarding the physiopathology of VCR-induced peripheral neuropathy (VIPN) and dapsone neuroprotection, this study evaluated the effect of dapsone on VIPN. METHODS: VIPN was induced by VCR injection (0.5 mg/kg IP, every other day, 1 week) in male Wistar rats. In the treatment group, dapsone(12.5 mg/kg IP, 1 week) was injected 30 min before VCR. Hot plate, Von Frey, motor neuron conduction velocity (MNCV), and histopathological tests were applied. The levels of TNF-α and NF-kB in the sciatic nerve and caspase-3 activity in dorsal root ganglion were measured by the ELISA method. The levels of malondialdehyde (MDA) and Glutathione (GSH) in the sciatic nerve were measured by spectrophotometry and colorimetric assays. RESULTS: VIPN was observed as araised thermal and mechanical threshold, reduced MNCV, and sciatic nerve demyelination. However, dapsone reduced the mechanical and thermal threshold and improved the MNCV. Also, dapsone reduced TNF-α, NF-kB, MDA, and Caspase-3 activity, and increased the GSH level in the sciatic nerve. Moreover, dapsone prevented VCR-induced demyelination in the sciatic nerve. CONCLUSION: This research demonstrated that dapsone could be used as a protective drug against VIPN. It improves the impaired thermal and mechanical sensations by reducing inflammatory, oxidant, and apoptosis factors and preventing demyelination in the sciatic nerve.

Cardioprotective effects of sodium thiosulfate against doxorubicin-induced cardiotoxicity in male rats.

BACKGROUND: Doxorubicin (DOX) is an effective antitumor agent, but its clinical usage is limited due to adverse cardiotoxic effects. Several compounds have been studied to reduce DOX cardiotoxicity to improve its therapeutic index. This study was aimed to investigate the protective effects of sodium thiosulfate (STS) pre-treatment against DOX-induced cardiomyopathy in rats. METHODS: Male Wistar rats were randomized into 4 groups: control (saline), DOX (2.5 mg/kg, 3 times per week, intraperitoneal [i.p.]), STS (300 mg/kg, 3 times per week, i.p), and DOX + STS (30 min prior to DOX injection, 3 times per week, i.p.) over a period of 2 weeks. The body weight, electrocardiography, histopathology, papillary muscle contractility, and oxidative stress biomarkers in heart tissues were assessed. RESULTS: The results indicated that STS significantly improved the body weight (P < 0.01), decreased QRS complex and QT interval on ECG (P < 0.05 and P < 0.001, respectively), as well as declined the papillary muscle excitation, and increased its contraction (P < 0.01) compared to DOX-treated rats. STS strongly suppressed oxidative stress induced by DOX through the significant improvement of the cardiac tissue antioxidant capacity by increasing glutathione, superoxide dismutase (P < 0.001), and decreasing the level of lipid peroxidation (P < 0.01). CONCLUSION: Taken together, the results of this study demonstrated that STS showed potent cardioprotective effects against DOX-induced cardiotoxicity by suppressing oxidative stress.

Sumatriptan improves the locomotor activity and neuropathic pain by modulating neuroinflammation in rat model of spinal cord injury.

OBJECTIVES: To investigate the therapeutic effects of sumatriptan in a rat model of spinal cord injury (SCI) and possible anti-inflammatory and analgesic mechanisms underlying this effect. METHODS: Using an aneurysm mini-clip model of contusive SCI, T9-10 laminectomies were performed for 60 male rats. Animals were divided into six experimental groups (n = 10 per group) as follows: a minocycline administered positive control group, a saline-vehicle negative control group, a sham-operated group, and three experimental groups which received separate doses of sumatriptan (0.1, 0.3 and 1 mg/kg). Behavioural assessments were used to evaluate locomotor activity and neuropathic pain for 28 days. At the end of the study, spinal cord tissues were collected from sacrificed animals for histopathological analysis. Levels of calcitonin gene-related peptide (CGRP) and two pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß) were assessed by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Sumatriptan significantly (P < 0.001) improved the locomotor activity in SCI group. Sumatriptan was also more effective than the positive control, i.e. minocycline (0.3 mg/kg). Additionally, sumatriptan and minocycline similarly attenuated the mechanical and thermal allodynia in SCI (P < 0.001). TNF-α, IL-1ß and CGRP levels in sumatriptan- and minocycline-treated groups significantly (P < 0.001) decreased compared to controls. Histopathological analysis also revealed a markedly improvement in hemorrhage followed by inflammatory cell invasion, neuronal vacuolation, and cyst formation in both sumatriptan- and minocycline-treated groups compared to control animals. CONCLUSIONS: Sumatriptan improves functional recovery from SCI through its anti-inflammatory effects and reducing pro-inflammatory and pain mediators.

Aripiprazole prevents from development of vincristine-induced neuropathic nociception by limiting neural NOS overexpression and NF-kB hyperactivation.

PURPOSE: Increased nitric oxide (NO) synthesis and NF-kB activation have been shown as critical players in the pathophysiology of vincristine-induced peripheral neuropathy. Consistently, neural nitric oxide synthase (nNOS) inhibitors alleviated the neuropathic pain. Previous studies demonstrated that aripiprazole is capable of modulating NO synthesis and also has been reported its modulatory effect on NF-kB activity. METHODS: Aripiprazole was administered daily to the male Wistar rats at the same time with establishing neuropathic model by I.P. injection of vincristine every 2 days, over 2 weeks. Efficacy of aripiprazole in suppressing the development of neuropathy was evaluated by assessing changes in body weight, mechanical threshold, withdrawal latency, sciatic nerve conduction velocity (SNCV), and compound motor action potential (CMAP) characteristics. Expression of nNOS and NF-kB activation were evaluated by western blotting RESULTS: Rats receiving aripiprazole during neuropathy establishment period demonstrated a normal weight gain pattern, a significantly higher mechanical withdrawal threshold, and SNCV compared to vincristine-treated group. Furthermore, the amplitude and area of CMAP were significantly higher in aripiprazole group. Western blotting demonstrated a significantly reduced expression of nNOS and NF-kB activation in dorsal root ganglia of aripiprazole co-treated rats. CONCLUSION: In conclusion, aripiprazole effectively prevents from vincristine-induced neuropathy by limiting nNOS overexpression and NF-kB hyperactivation.

The protective effects of sumatriptan on vincristine - induced peripheral neuropathy in a rat model.

Clinical use of vincristine (VCR), an effective chemotherapeutic agent, has been limited due to its peripheral neuropathy toxicity. Sumatriptan, which is an anti-migraine agent is a specific agonist for 5-hydroxytryptamine 1B, 1D (5HT1B, 1D) receptors. Several studies have shown that sumatriptan exerts anti-inflammatory and immunomodulatory properties. This study aimed to investigate the effects of sumatriptan on VCR-induced peripheral neuropathy in a rat model. Male Wistar rats were intraperitoneally injected with VCR and normal saline four times per week for 2 weeks. In the treatment group, sumatriptan (1 mg/kg) was administered intraperitoneally 30 min prior to VCR injection every day. Mortality rate, weight variations and histopathological changes were monitored. Hot plate, tail flick and motor nerve conduction velocity (MNCV) tests were used to evaluate sensory and motor neuropathy. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß) and caspase-3 in the dorsal ganglion root were assessed by quantitative reverse transcription-PCR (qRT-PCR). Moreover, the protein levels of p65 nuclear factor kappa B (NF- B) and phospho-p65 NF- B were examined by Western blot analysis. Co-administration of sumatriptan with VCR significantly reversed alterations in the hot plate, tail flick threshold and sciatic MNCV induced by VCR and also prevented mixed sensory-motor neuropathy, as indicated by better general conditions, behavioral and electrophysiological results. In addition, sumatriptan improved the body weight loss caused by VCR. The mRNA levels of TNF-α, IL-1ß and caspase-3 were significantly diminished in the treatment group. These findings were confirmed by histopathological analysis. In conclusion, this study demonstrated that sumatriptan significantly attenuated VCR-induced neuropathy and could be considered as a neuroprotective agent to prevent the VCR-induced neuropathy.

Protective effects of magnesium sulfate against doxorubicin induced cardiotoxicity in rats.

AIMS: Clinical use of doxorubicin, an effective chemotherapeutic agent, has limited uses due to dose-dependent cardiac toxicity. It has been supposed that the production of free radicals and calcium ions overload can lead to cardiac toxicity. Magnesium is a cardioprotective drug which inhibits lipid peroxidation and reducing myocardial apoptosis. This study was aimed to explore the hypothesis that the cardiac toxicity induced by administration of doxorubicin is prevented or reduced by magnesium sulfate treatment and if so, whether this is associated with altered oxidative stress response in heart. MATERIAL AND METHODS: Male Wistar rats were intraperitoneally injected with doxorubicin and magnesium sulfate and normal saline four times per week for 2 consecutive weeks. Then electrocardiographic, inotropic and biochemical tests were performed. KEY FINDINGS: Co-administration of magnesium sulfate with doxorubicin significantly reversed alterations in the stimulation threshold and contractile force induced by doxorubicin. In addition, magnesium sulfate improved body weight loss and alleviated the mortality rate of animals induced by doxorubicin. Moreover, it was observed that lesions induced by doxorubicin decreased in animals treated with magnesium sulfate. Magnesium sulfate significantly increased Glutathione (GSH) in doxorubicin treated animals. SIGNIFICANCE: In conclusion, the results of the present study demonstrated that magnesium sulfate attenuate the cardio toxic effects of doxorubicin by increasing the activities of the antioxidants enzyme.