الفهرس 
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Abstract
Epilepsy is a neurological disorder characterized by recurrent seizures. Seizures are caused by abnormal electrical activity in the brain. There are several different types of seizures, and the treatment plan depends on the type of seizures a person is experiencing. The treatment options for epilepsy include antiepileptic drugs (AEDs) which are the mainstay of treatment for epilepsy. These drugs relief the symptoms of seizures and work by altering the electrical activity in the brain and can help to prevent seizures. Examples of AEDs include phenytoin, carbamazepine (CBZ), valproic acid, and lamotrigine. Some people with epilepsy may turn to alternative therapies, such as acupuncture, massage, or herbal supplements, to reduce seizures. However, there is limited scientific evidence to support the use of these therapies. One of these therapies is Astaxanthin (AST) which may mitigate epilepsy–induced oxidative stress and neuronal necrosis in the brain. Nano lipid carriers (NLCs) serve as better drug delivery carriers for lipophilic drugs such as CBZ and AST.
On the present study aimed to establish rat model of epilepsy-like disease (SE-like) using the LiCl-pilocarpine then using these rat model to evaluate the therapeutic potential of AST and/or CBZ as a solution form or loaded on NLCs by intranasal administration. Also, to explore the possible molecular targets of AST and the combination of AST+CBZ as nano-formulation.
The study was conducted on seventy-two (72) adult male albino rats divided into two main groups, group I (control group): consists of 8 normal male rats. group II (SE-like rats): 64 epileptic rats in which the epilepsy was induced by intraperitoneal injection of lithium chloride (127.3 mg/kg in 0.9% saline), 24-hour before the intraperitoneal injection of pilocarpine (30 mg/kg). Thirty minutes before pilocarpine injection, scopolamine (1 mg/kg) was injected. After the establishment of SE, rats were subdivided into 8 groups (8 rats each): group IIA: untreated SE-like rats, group IIB: SE-like rats treated intranasally with 10 µl of NLC (vehicle) in each nostril, group IIC: SE-like rats treated intranasally with AST solution (4mg/kg) in each nostril, group IID: SE-like rats treated intranasally with CBZ (2mg/kg) in each nostril, group IIE: SE-like rats treated intranasally with
combination of AST (4mg/kg) and CBZ (2mg/kg) in each nostril, group IIF: SE-like rats treated intranasally with AST-NLCs (4mg/kg) in each nostril, group IIG: SE-like rats treated intranasally with CBZ-NLCs (2mg/kg) in each nostril, and group IIH: SE-like rats treated intranasally with combination of AST+CBZ-NLCs in each nostril. All rats were treated daily for 4 weeks.
After the duration of therapy was already over, the rats were examined by the behavioral tests; rotarod test and Morris Water Maze (MWM) and then sacrificed and the brains were dissected out to obtain cerebral cortex and hippocampus for the assessment of neurotransmitters; GABA, serotonin and dopamine; gene expression of GABAA receptors subunits and gephyrin; inflammatory markers: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and High mobility group box 1 (HMGB1) and antioxidant markers: nuclear factor transcription factor E2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1).
In the present study we designed, prepared, and characterized a candidate of anti-epileptics drugs (AST and/or CBZ) loaded on NLCs. The optimized NLCs formulation was evaluated for particle size (PS), polydisperasity index (PDI), zeta potential (ZP), and entrapment efficiency. The results showed that SE-like rats treated intranasally with AST and/or CBZ as solutions or nano-formulations showed significantly better performance in the rotarod and MWM than the untreated rats with no significant difference between the effect of each of the two drugs alone or in combination as solution or nano-formulation. At the histological and morphometric levels, both drugs as NLC-nano-formulations showed a remarkable improvement in the pathological alterations including degenerate and necrotic neurons in both cortex and hippocampus tissues compared with the untreated SE-like rats with the best results obtained in the rats treated with nano-formulation of the combined drugs (AST+CBZ).
At the GABAergic neurotransmission level, AST alone or combined with CBZ as nano-formulations significantly and completely normalized GABA contents in both cortex and hippocampus compared with the untreated SE-like rats and rats treated, with the best possible ameliorative effects showed in those rats medicated by combined drugs in NLC-formulation. The derangements in the expression of GABAA receptor subunits (α1, α5, β1, β2, and γ2) in SE-like rats were generally ameliorated by the AST and/or CBZ nano-formulations treatment, while the solution forms of both drugs showed no significant effects or mild effects when combined.
AST nano-formulations significantly increased the cortical serotonin, and hippocampal DA. Also, treatment of SE-like rats with AST alone or combined with CBZ (as solutions or nano-formulations) showed anti-neuroinflammatory potentials as indicated by the marked reduction in the cortical and hippocampal levels of NF-κB and HMGB1. The observed neurological effects of AST (as solutions or nano-formulations) may be a consequence of the antioxidant boosting effects of AST as indicated by marked increase in the expression of Nrf2 and its target gene HO-1 in both cortex and hippocampus of SE-like rats treated with AST alone or combined with CBZ.