Effect of Lenalidomide on Pentylenetetrazole-Induced Clonic Seizure Threshold in Mice: A Role for N-Methyl-D-Aspartic Acid Receptor/Nitric Oxide Pathway.

BACKGROUND AND PURPOSE: Accumulating evidence suggest that lenalidomide, a structural analog of thalidomide, has neuro-modulatory and neuroprotective properties. In the present study, we investigated effects of acute administration of lenalidomide on clonic seizure threshold in mice induced by pentylenetetrazole (PTZ) and possible role of N-methyl-D-aspartic acid receptor (NMDAR) and nitric oxide (NO) pathway. METHODS: We have utilized a clonic model of seizure in NMRI mice induced by PTZ to evaluate the potential effect of lenalidomide on seizure threshold. Different doses of lenalidomide (5, 10, 20, and 50 mg/kg, intraperitoneal [i.p.]) were administered 1 hour before PTZ. To evaluate probable role of NMDAR/NO signaling, the non-selective NO synthase inhibitor L-N G-nitroarginine methyl ester (L-NAME; 10 mg/kg, i.p.), neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI; 30 mg/kg, i.p.), selective inducible NOS inhibitor aminoguanidine (AG; 100 mg/kg, i.p.), selective NMDAR antagonist MK-801 (0.01 mg/kg, i.p.), and selective NMDAR agonist D-serine (30 mg/kg, i.p.) were injected 15 minutes before lenalidomide. RESULTS: Lenalidomide at 10 and 20 mg/kg significantly elevated the PTZ-induced seizure thresholds. Interestingly, L-NAME (10 mg/kg, i.p), 7-NI (30 mg/kg, i.p), and AG (100 mg/kg, i.p) reversed the anticonvulsive effect of lenalidomide (10 mg/kg). Moreover, treatment with the NMDAR agonist D-serine (30 mg/kg, i.p.) did not alter the anticonvulsive properties of lenalidomide (10 mg/kg, i.p). However, the NMDAR antagonist MK-801 (0.01 mg/kg, i.p) significantly reversed the anticonvulsive effects of lenalidomide (10 mg/kg). CONCLUSIONS: Our study demonstrated a role for the NMDAR/NO pathway in the anticonvulsive effects of lenalidomide on the PTZ-induced clonic seizures in mice.

Severe Relapses of Neuromyelitis Optica Spectrum Disorder During Treatment With Dimethyl Fumarate.

ABSTRACT: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system, characterized by a specific antibody that selectively binds aquaporin-4 channel.This is a report of an NMOSD case, with severe attacks of optic neuritis and myelitis after initiate of dimethyl fumarate (DMF).We suggested that DMF could deteriorate the neuromyelitis optica (NMO) disease course, which results in serious morbidity and mortality in patients. Thus, initiation of DMF should be avoided before ruling out NMOSD in patients experiencing demyelinating attacks, especially in the case of recurrent optic neuritis or myelopathy and concurrency of other rheumatologic diseases.

Isolated severe thrombocytopenia in a patient with COVID-19: A case report.

COVID-19 is known to cause serious respiratory symptoms and involvement of other body systems such as hematopoietic, neurological and the immune system. In this report, we described a case of a COVID-19 patient who presented with no pulmonary involvement but severe thrombocytopenia. She suffered from headache and malaise with no respiratory symptoms, fever or chills. Chest radiological imaging was unremarkable but, the laboratory results showed significant thrombocytopenia associated with relatively decreased lymphocytes. Based on her high-risk work environment, a reverse transcription polymerase chain reaction (RT-PCR) test was performed and SARS-CoV-2 RNA was detected in the nasopharyngeal swab. Complete blood count (CBC) of patient was re-checked during admission and platelet count showed rising trend up to normal levels. A narrow diagnostic approach where only febrile patients with pulmonary symptoms are evaluated for a COVID-19 diagnosis will result in many missed diagnoses; so it is important that physicians are familiar with atypical and rare presentations of COVID-19, such as isolated thrombocytopenia.

Adjuvant potential of selegiline in treating acute toxicity of aluminium phosphide in rats.

Aluminium phosphide (AlP) is a highly toxic substance with a high mortality rate and no effective antidote. Once exposed to the moisture and acidic conditions of the stomach, AlP releases toxic phosphine (PH3 ) gas, which results in severe toxicity in poisoned subjects. Selegiline is a monoamine oxidase inhibitor with antioxidant and anti-apoptotic properties, which is mostly prescribed for the treatment of mood disorders and Parkinson's disease. Since AlP has detrimental effects on cardiac physiology and mitochondrial function, we tested the protective effects of acute selegiline treatment on cardiac mitochondrial function, redox status and electrocardiographic parameters in rats after AlP poisoning. To do this, AlP was given to rats by gavage to induce toxicity. Selegiline was injected intraperitoneally in the treatment groups 1 hour after AlP poisoning. Selegiline treatment after AlP intoxication was not associated with a significant difference in the mortality rate of animals. However, selegiline reduced oxidative stress (decreased the reactive oxygen species and malondialdehyde) and increased glutathione in the cardiac tissue of rats exposed to AlP. Further, the mitochondrial membrane potential (ΔΨm) collapse reversed after treatment with selegiline. Selegiline also improved the electrocardiographic (ECG) parameters and enhanced heart rate. The histopathological evaluation revealed that selegiline eliminated the inflammation and injuries induced by AlP in the stomach and duodenum, as well as cardiac tissue. In conclusion, selegiline treatment can ameliorate the AlP-induced cardiac and gastrointestinal injuries in rats via boosting redox status and mitochondrial function with no significant effect on survival. We suggest that using selegiline, apart from other clinical treatments, may improve the quality of treatment process for AlP toxicity.

Convergent effects of a functional C3 variant on brain atrophy, demyelination, and cognitive impairment in multiple sclerosis.

BACKGROUND: Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity. OBJECTIVES: To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures. METHODS: In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) ≤ 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy ( n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90). RESULTS: While rs2230199 minor-allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance ( p = 0.02), lower brain parenchymal fraction ( p = 0.003), and higher lesion burden ( p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele. CONCLUSION: C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS.

Involvement of central opioid receptors in protective effects of methadone on experimental colitis in rats.

PURPOSE: There are several lines of evidence on the protective roles of opioids in gastrointestinal inflammatory conditions. This study aims to distinguish the central and peripheral roles of methadone, a non-selective opioid receptor agonist, in an acute model of ulcerative colitis in male rats. METHODS: Ulcerative colitis was induced by intrarectal administration of acetic acid 4%. Methadone was injected subcutaneously (s.c.), 5 and 10 mg/kg, and intracerebroventricular (i.c.v.), 50 and 300 ng/rat. Opioid antagonists were employed. Methylnaltrexone (MNTX; 5 mg/kg, i.p.), a peripherally acting opioid receptor antagonist, and naltrexone (NTX; 5 mg/kg, i.p. and 10 ng/rat, i.c.v.), a peripherally and centrally acting opioid receptor antagonist were injected before methadone (10 mg/kg, s.c. and or 300 ng/rat, i.c.v.) administration. NTX (5 mg/kg, i.p. and 10 ng/rat, i.c.v.) were administered 30 min prior to administration of methadone (10 mg/kg, s.c. and 300 ng/rat, i.c.v.), respectively. MNTX (5 mg/kg, i.p.) was injected 30 min prior to methadone (10 mg/kg, s.c.). Seventy-two hours following colitis induction, macroscopic and microscopic mucosal lesions, and the colonic levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) were determined. RESULTS: Methadone (300 ng/rat, i.c.v.) and Methadone (5 and 10 mg/kg, s.c.) improved the macroscopic and microscopic scores through opioid receptors. Also, a significant reduction in TNF-α and IL-1ß was observed. Peripherally and centrally injected NTX significantly reversed methadone 10 mg/kg s.c. anti-inflammatory effects while MNTX could not completely reverse this effect. Moreover, centrally administered methadone (300 ng/rat) showed the anti-inflammatory effect which was reversed by central administration of NTX (10 ng/rat). CONCLUSIONS: The opioid receptors mainly the central opioid receptors may mediate the protective actions of methadone on the experimental model of inflammatory bowel disease in rat.

Fresh red blood cells transfusion protects against aluminum phosphide-induced metabolic acidosis and mortality in rats.

BACKGROUND: Aluminum phosphide (AlP) is used as pesticide in some countries for protection of stored grains. Human poisoning with AlP due to suicide attempt or accidental environmental exposure is associated with very high mortality partially due to development of severe metabolic acidosis. Previous studies have shown that hemoglobin has high buffering capacity and erythrocytes can potentially be used for management of metabolic acidosis. The aim of this study was to evaluate the effect of fresh packed red blood cells (RBC) transfusion on survival and cardiovascular function in AlP-poisoned rats. METHODOLOGY/PRINCIPAL FINDINGS: Rats were poisoned with AlP by gavage. Fresh packed RBC was transfused via tail vein after AlP administration. Acid-base balance, vital signs and mortality was assessed and compared in experimental groups. Infusion of fresh packed RBC (1.5 ml) one hour after AlP (4-15 mg/kg) intoxication was associated with a significant decrease in mortality rate. Packed RBC infusion improved blood pH, HCO3-, Na+ and Ca2+ levels. Plasma troponin level was also reduced and ECG changes were reversed following packed RBC infusion in AlP intoxicated rats. CONCLUSIONS: Our results showed that fresh RBC transfusion could ameliorate metabolic acidosis and enhance survival in AlP-poisoned rat. We assume that an increase in pool of RBCs may modulate acid-base balance or potentially chelate AlP-related toxic intermediates via phosphine-hemoglobin interaction.

Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat.

The detrimental cardio-toxic effect of doxorubicin, an effective chemotherapeutic agent, limited its clinical use. It has been claimed that doxorubicin cardio-toxicity occurs through calcium ions (Ca2+) overload and reactive oxygen species production. Agmatine, an endogenous imidazoline receptor agonist, induce uptake of cytosolic Ca2+ and cause an increase in activity of calcium pumps, including Ca2+-ATPase. Also it shows self-scavenging effect against reactive oxygen species production. Therefore, present study was designed to investigate the effects of agmatine against chronic cardio-toxicity of doxorubicin in rats. Male wistar rats were intraperitoneally injected with doxorubicin and agmatine four times a week for a month. Agmatine significantly alleviate the adverse effect of doxorubicin on left ventricular papillary muscle stimulation threshold and contractibility. Chronic co-administration of agmatine with doxorubicin blocked electrocardiographic changes induced by doxorubicin. In addition, agmatine improved body weight and decreased the mortality rate of animals by doxorubicin. Moreover, reversing the doxorubicin induced myocardial lesions was observed in animals treated by agmatine. A significant rise in the total antioxidant capacity of rat plasma was achieved in agmatine-treated animals in comparison to doxorubicin. To conclude, agmatine may improve therapeutic outcomes of doxorubicin since it exerts protective effects against doxorubicin-induced chronic cardiotoxicity in rats.

The modulatory effect of nitric oxide in pro- and anti-convulsive effects of vasopressin in PTZ-induced seizures threshold in mice.

Vasopressin neuropeptides play an important role in the several cognitive, social, and neuroendocrine functions. Also, several studies report the involvement of nitrergic system in the vasopressin functions in central nervous system. This study investigates the effect of Arginine-Vasopressin (AVP) in pentylenetetrazol (PTZ)-induced seizures threshold and the probable role of nitric oxide (NO). AVP is administered intraperitoneally (0.01-20µg/kg, i.p.) 30min before induction of seizures. Administration of AVP (0.1µg/kg) significantly lowered the PTZ-induced seizures threshold. But, administration of AVP (10 and 20µg/kg) increased the seizures threshold, significantly. Pretreatment of SR 49059 (V1a receptor antagonist, 2mg/kg, i.p.) just reversed the pro-convulsant effect of AVP. Meanwhile, SSR 149415 (V1b receptor antagonist, 10mg/kg, i.p.) pretreatment reversed both pro-and anti-convulsant effects of AVP. The nitric oxide precursor, L-arginine (60mg/kg, i.p.) increased pro-convulsant effect of AVP, but did not change anticonvulsant activity. The nitric oxide synthase (NOS) inhibitor L-NAME (10mg/kg, i.p.) reversed both pro- and anti-convulsant effect of AVP. Selective inducible NOS inhibitor, aminoguanidine (100mg/kg, i.p.) just reversed the anti-convulsant effects of AVP. The results of the present study showed nitric oxide system may contribute to the biphasic effects of AVP on PTZ-induced seizures. V1a receptor may modulate only the proconvulsive effect. While, V1b receptors can mediate both the pro- and anti-convulsive effect of AVP.