Ivermectin Exerts Anticonvulsant Effects Against Status Epilepticus Induced by Lithium-Pilocarpine in Rats via GABAA Receptor and Neuroinflammation Modulation: Possible Interaction of Opioidergic Pathways and KATP Channel with Nitrergic System.

Status epilepticus (SE) is a critical medical emergency marked by persistent or rapidly repeating seizures, posing a threat to life. Using the lithium-pilocarpine-induced SE model, we decide to evaluate the anti-seizure effects of ivermectin as a positive allosteric modulator of GABAA receptor and the underlying mechanisms involved. Lithium chloride was injected intraperitoneally at a dose of 127 mg/kg, followed by the administration of pilocarpine at a dose of 60 mg/kg after a 20-h interval in order to induce SE. Subsequently, the rats received varying amounts of ivermectin (0.3, 1, 3, 5, and 10 mg/kg, i.p.) 30 min before the onset of SE. To study the underlying molecular mechanisms, we had pharmacological interventions of diazepam (1 mg/kg), glibenclamide and nicorandil as ATP-sensitive potassium channel blocker and opener (both 1 mg/kg, i.p.), naltrexone and morphine, as opioid receptor antagonist and agonist (1 mg/kg and 0.5 mg/kg, i.p., respectively). In addition, three nitric oxide inhibitors, namely, L-NAME (10 mg/kg, i.p.), 7-NI (30 mg/kg, i.p.), and aminoguanidine (100 mg/kg, i.p.), were administered to the rats in the experiment. Finally, we use ELISA and western blotting, respectively, to examine the amounts of pro-inflammatory cytokines (TNF-α and IL-1ß), nitrite, and GABAA receptors in the rat hippocampal tissue. The study found that ivermectin, at doses of 3, 5, and 10 mg/kg, exerts anti-seizure effects and decrease Racine's scale SE score. Interestingly glibenclamide and naltrexone reduced the anti-seizure effects of ivermectin, and from other hand diazepam, nicorandil, morphine, L-NAME, 7-NI, and aminoguanidine, enhance the effects when co-administrated with subeffective dose of ivermectin. Additionally, the study found that ivermectin decreased the elevated levels of TNF-α and IL-1ß following SE, while increased the reduced expression of GABAA receptors. Overall, these findings suggest that ivermectin has anti-seizure effects in a SE seizure which may be mediated by the modulation of GABAergic, opioidergic, and nitrergic pathways and KATP channels.

Retinal and Choroidal Neovascularization Antivascular Endothelial Growth Factor Treatments: The Role of Gene Therapy.

Neovascularization in ocular vessels causes a major disease burden. The most common causes of choroidal neovascularization (CNV) are age-related macular degeneration and diabetic retinopathy, which are the leading causes of irreversible vision loss in the adult population. Vascular endothelial growth factor (VEGF) is critical for the formation of new vessels and is the main regulator in ocular angiogenesis and vascular permeability through its receptors. Laser therapy and antiangiogenic factors have been used for CNV treatment. Bevacizumab, ranibizumab, and aflibercept are commonly used anti-VEGF agents; however, high costs and the need for frequent intraocular injections are major drawbacks of anti-VEGF drugs. Gene therapy, given the potency of one-time treatment and no need for frequent injections offers the real possibility of such a lasting treatment, with fewer adverse effects and higher patient quality of life. Herein, we reviewed the role of gene therapy in the CNV treatment. In addition, we discuss the advantages and challenges of current treatments compared with gene therapy.

Type 2 Diabetes Mellitus and Alzheimer's Disease: A Review of the Potential Links.

Diabetes mellitus and Alzheimer's disease are considered the most prevalent diseases in older ages worldwide. The main pathology of Alzheimer's disease is highly related with accumulation of misfolded proteins that lead to neuronal dysfunction in the brain. On the other hand, diabetes mellitus is associated with alteration of insulin signaling, which could cause the reduction of glucose uptake, metabolic prohibition of energy consuming cells, as well as suppression of glucose to fat conversion in the liver. In spite of having seemingly different pathological features, both diseases share common underlying biological mechanisms. Besides, the epidemiological and environmental links between these two diseases should not be overlooked. In this study, we aim to review shared pathological mechanisms of Alzheimer's disease and diabetes mellitus, including impaired glucose metabolism, increased Amyloid-Beta (Aß) production, impaired lipid metabolism, mitochondrial dysfunction, increased inflammation and elevated oxidative stress. Furthermore, we discuss epidemiological association between these two diseases and also review animal investigations, which have evaluated the potential links between the two diseases.