Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India.
Neurochem Res. 2024 Jun;49(6):1556-1576. doi: 10.1007/s11064-023-04082-9. Epub 2023 Dec 30.
Multiple sclerosis (MS) is a pathological condition characterized by the demyelination of nerve fibers, primarily attributed to the destruction of oligodendrocytes and subsequent motor neuron impairment. Ethidium bromide (EB) is a neurotoxic compound that induces neuronal degeneration, resulting in demyelination and symptoms resembling those observed in experimental animal models of multiple sclerosis (MS). The neurotoxic effects induced by EB in multiple sclerosis (MS) are distinguished by the death of oligodendrocytes, degradation of myelin basic protein (MBP), and deterioration of axons. Neurological complications related to MS have been linked to alterations in the signaling pathway known as smo-shh. Purmorphine (PUR) is a semi-synthetic compound that exhibits potent Smo-shh agonistic activity. It possesses various pharmacological properties, including antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory effects. Hence, the current investigation was conducted to assess the neuroprotective efficacy of PUR (at doses of 5 and 10 mg/kg, administered intraperitoneally) both individually and in conjunction with Fingolimod (FING) (at a dose of 0.5 mg/kg, administered intraperitoneally) in the experimental model of MS induced by EB. The administration of EB was conducted via the intracerebropeduncle route (ICP) over a period of seven days in the brain of rats. The Wistar rats were allocated into six groups using randomization, each consisting of eight rats (n = 8 per group). The experimental groups in this study were categorized as follows: (I) Sham Control, (II) Vehicle Control, (III) PUR per se, (IV) EB, (V) EB + PUR5, (VI) EB + PUR10, (VII) EB + FING 0.5, and (VIII) EB + PUR10 + FING 0.5. On the final day of the experimental timeline, all animal subjects were euthanized, and subsequent neurochemical estimations were conducted on cerebrospinal fluid, blood plasma, and brain tissue samples. In addition, we conducted neurofilament (NFL) analysis and histopathological examination. We utilized the luxol myelin stain to understand better the degeneration associated with MS and its associated neurological complications. The findings of our study indicate that the activation of SMO-Shh by PUR has a mitigating effect on neurobehavioral impairments induced by EB, as well as a restorative effect on cellular and neurotransmitter abnormalities in an experimental model of MS.
多发性硬化症（MS）是一种病理状况，其特征在于神经纤维的脱髓鞘，主要归因于少突胶质细胞的破坏和随后的运动神经元损伤。溴化乙锭（EB）是一种神经毒性化合物，可诱导神经元变性，导致脱髓鞘和类似于实验性多发性硬化症（MS）动物模型中观察到的症状。EB 在多发性硬化症（MS）中引起的神经毒性作用的特征在于少突胶质细胞的死亡、髓鞘碱性蛋白（MBP）的降解以及轴突的恶化。与 MS 相关的神经并发症与称为 smo-shh 的信号通路的改变有关。Purmorphine（PUR）是一种具有强大 Smo-shh 激动活性的半合成化合物。它具有多种药理学特性，包括抗氧化、抗炎、抗细胞凋亡和神经调节作用。因此，本研究旨在评估 PUR（以 5 和 10mg/kg 的剂量腹腔内给药）单独和与 Fingolimod（FING）（以 0.5mg/kg 的剂量腹腔内给药）联合在 EB 诱导的 MS 实验模型中的神经保护作用。通过脑内脑干部位（ICP）途径在大鼠脑内连续七天给予 EB。Wistar 大鼠采用随机分组法分为六组，每组 8 只大鼠（每组 n=8）。本研究的实验组分为以下几类：（I）假对照，（II）载体对照，（III）PUR 本身，（IV）EB，（V）EB+PUR5，（VI）EB+PUR10，（VII）EB+FING 0.5，和（VIII）EB+PUR10+FING 0.5。在实验时间表的最后一天，所有动物均被安乐死，随后对脑脊液、血浆和脑组织样本进行神经化学评估。此外，我们还进行了神经丝（NFL）分析和组织病理学检查。我们使用卢索尔髓鞘染色来更好地了解与 MS 相关的神经退行性变及其相关的神经并发症。我们的研究结果表明，PUR 对 SMO-Shh 的激活对 EB 诱导的神经行为损伤具有缓解作用，并对 MS 实验模型中的细胞和神经递质异常具有恢复作用。
