CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 21, Issue 8, 2022

Parkinson´s Disease (PD) is the second most common neurodegenerative disorder, affecting ∼2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy Bodies (LBs). Recently, Genome-Wide Association Studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

Neurodevelopmental Disorders (NDDs) are abnormalities linked to neuronal structure and irregularities associated with the proliferation of cells, transportation, and differentiation. NDD also involves synaptic circuitry and neural network alterations known as synaptopathy. Microtubules (MTs) and MTs-associated proteins help to maintain neuronal health as well as their development. The microtubular dynamic structure plays a crucial role in the division of cells and forms mitotic spindles, thus take part in initiating stages of differentiation and polarization for various types of cells. The MTs also take part in cellular death, but MT-based cellular degenerations are not yet well excavated. In the last few years, studies have provided the protagonist activity of MTs in neuronal degeneration. In this review, we largely engrossed our discussion on the change of MT cytoskeleton structure, describing their organization, dynamics, transportation, and their failure causing NDDs. At the end of this review, we are targeting the therapeutic neuroprotective strategies on clinical priority and also try to discuss the clues for the development of new MT-based therapy as a new pharmacological intervention. This will be a new potential site to block not only neurodegeneration but also promotes the regeneration of neurons.

Background and Objectives: Experimental Autoimmune Encephalomyelitis (EAE) in rats closely reproduces Multiple Sclerosis (MS), a disease characterized by neuroinflammation and oxidative stress that also appears to extend to other organs and their compartments. The origin of MS is a matter for discussion, but it would seem that altering certain bacterial populations present in the gut may lead to a proinflammatory condition due to the bacterial Lipopolysaccharides (LPS) in the so-called brain-gut axis. The casein and lactose in milk confer anti-inflammatory properties and immunomodulatory effects. The objectives of this study were to evaluate the effects of administration of casein and lactose on the oxidative damage and the clinical status caused by EAE and to verify whether both casein and lactose had any effect on the LPS and its transport protein -LBP-. Methods: Twenty male Dark Agouti rats were divided into control rats (control), EAE rats, and EAE rats, to which casein and lactose, EAE+casein, and EAE+lactose, respectively, were administered. Fifty-one days after casein and lactose administration, the rats were sacrificed, and different organs were studied (brain, spinal cord, blood, heart, liver, kidney, small, and large intestine). In the latter, products derived from oxidative stress were studied (lipid peroxides and carbonylated proteins) as well as the glutathione redox system, various inflammation factors (total nitrite, Nuclear Factor-kappa B p65, the Rat Tumour Necrosis Factor-α), and the LPS and LBP values. Results and Conclusion: Casein and lactose administration improved the clinical aspect of the disease at the same time as reducing inflammation and oxidative stress, exerting its action on the glutathione redox system, or increasing GPx levels.

Background: Upregulation of mitochondrial E3 ubiquitin ligase 1 (Mul1) contributes to brain injury in ischemic stroke due to disturbance of mitochondrial dynamics, and bioinformatics analysis predicts that Mul1 is a potential target of Dipsacoside B. Objective: The aim of the study was to explore whether Dipsacoside B can exert a beneficial effect on brain injury in the ischemic stroke rat via targeting Mul1. Methods: The SD rat brains or PC12 cells were subjected to 2 h-ischemia or 8 h-hypoxia plus 24 h-reperfusion or 24 h-reoxygenation to establish the ischemic stroke rat model in vivo or in vitro, which were treated with Dipsacoside B at different dosages. The brain or PC12 cell injury, relevant protein levels and mitochondrial functions were measured by methods of biochemistry, flow cytometry or Western blot. Results: The neurological dysfunction and brain injury (such as infarction and apoptosis) observed in the ischemic stroke rats were accompanied by increases in Mul1 and Dynamin-related protein 1 (Drp1) levels along with decreases in mitofusin 2 (Mfn2) level and ATP production. These effects were attenuated by Dipsacoside B. Consistently, cell injury (necroptosis and apoptosis) occurred in the PC12 cells exposed to hypoxia concomitant with the upregulation of Mul1 and Drp1 along with downregulation of Mfn2 and mitochondrial functions (such as increases in reactive oxygen species production and mitochondrial fission and decreases in mitochondrial membrane potential and ATP production).These phenomena were reversed in the presence of Dipsacoside B. Conclusion: Dipsacoside B can protect the rat brain against ischemic injury via inhibition of Mul1 due to the improvement of mitochondrial function.

Background: Atomoxetine is a treatment for attention-deficit hyperactivity disorder. It inhibits Norepinephrine Transporters (NET) in the brain. Renal impairment can reduce hepatic CYP2D6 activity and atomoxetine elimination which may increase its body exposure. Atomoxetine can be secreted in saliva. Objective: The objective of this work was to test the hypothesis that atomoxetine saliva levels (sATX) can be used to predict ATX brain Extracellular Fluid (bECF) levels and their pharmacological effects in healthy subjects and those with End-Stage Renal Disease (ESRD). Methods: The pharmacokinetics of atomoxetine after intravenous administration to rats with chemically induced acute and chronic renal impairments were investigated. A physiologically-based pharmacokinetic (PBPK) model was built and verified in rats using previously published measured atomoxetine levels in plasma and brain tissue. The rat PBPK model was then scaled to humans and verified using published measured atomoxetine levels in plasma, saliva, and bECF. Results: The rat PBPK model predicted the observed reduced atomoxetine clearance due to renal impairment in rats. The PBPK model predicted atomoxetine exposure in human plasma, sATX and bECF. Additionally, it predicted that ATX bECF levels needed to inhibit NET are achieved at 80 mg dose. In ESRD patients, the developed PBPK model predicted that the previously reported 65% increase in plasma exposure in these patients can be associated with a 63% increase in bECF. The PBPK simulations showed that there is a significant correlation between sATX and bECF in human. Conclusion: Saliva levels can be used to predict atomoxetine pharmacological response.

Background: Attention Deficit Hyperactivity Disorder is a common child neurobehavioral disorder whose pathogenesis is not completely understood. However, some evidence indicates a crucial link between this disorder and the degree of oxidative stress. Coenzyme Q10 (ubiquinol) is an antioxidant that may play a significant role in the treatment of Attention Deficit Hyperactivity Disorder. Objective: To assess the safety and efficacy of coenzyme Q10 as an add-on drug treatment for attention deficit hyperactivity disorder. Methods: Sixty children, aged 6-16 years, with attention deficit hyperactivity disorder, non-responders to atomoxetine treatment for 6 months, were included in this double-blind, randomized, and controlled study. Group 1 received atomoxetine plus coenzyme Q10, and group 2 received atomoxetine plus placebo for 6 months. Follow-up by CONNERS parent rating scale questionnaire (CPRS-48) was performed before and after 1, 3, and 6 months of treatment, and any drug-related side effects were reported. Results: The addition of coenzyme Q10 to atomoxetine in group 1 improved symptoms in a shorter time with minimal adverse effects. Group 1 showed improvement of about 33.87% in CPRS-48 total score versus 18.24% in group 2. There was a statistically significant decrease in CPRS-48 total score and its three subscales (learning problems, impulsive hyperactive subscale, and 10-items hyperactivity index) in group 1 versus group 2 after six months of treatment (p-value <0.001). Conclusion: Coenzyme Q10 has an important role as an add-on drug treatment for attention deficit hyperactivity disorder by improving symptoms, particularly hyperactivity, and in minimizing atomoxetine adverse effects.

Background: In this double-blinded randomized clinical trial, we aimed to compare the safety and efficacy of a combination of Dexmedetomidine and Ketamine (DK) with Propofol and Fentanyl (PF) for sedation in colonoscopy patients. Methods: In this study, 64 patients who underwent colonoscopy were randomized into two groups: 1) A, which received PF, and 2) B, which received DK for sedation. Among 64 patients, 31 patients were included in PF, and 33 patients were included in the DK group. Both groups were similar in terms of demographics. Patients’ sedation score (based on Ramsay sedation scale) and vital signs were recorded at 2, 5, 10, and 15 minutes. Complications including apnea, hypotension, hypoxia, nausea, and vomiting, along with gastroenterologist satisfaction and patients’ pain score (based on Wong-Baker faces pain assessment scale), were recorded by a checklist. Data were analyzed by SPSS v.18 software, using chi-square, independent t-tests, and repeated measures analysis with p<0.05 as the criterion for significant differences. Results: The mean score of sedation was 4.82±0.49 in the DK group and 5.22±0.45 in the PF group (p value=0.001). Serious complications, including hypotension (p value=0.005) and apnea (p value=0.10) were significantly higher in the PF group. Satisfaction of gastroenterologist (p value= 0.400) and patients’ pain score (p value = 0.900) were similar among groups. Conclusion: Combination of DK provides sufficient sedation with fewer complications in comparison with PF in colonoscopy patients.