CNS & Neurological Disorders - Drug Targets - Volume 21, Issue 6, 2022

Background: Migraine is a highly prevalent primary headache with an unclear pathomechanism. During the last 40 years, numerous hypotheses have arisen; among them, the theory of the trigeminovascular system is the primary one. It serves as a skeleton in successful preclinical studies and in the development of effective therapeutic options for migraine headache. Objective: The brain prize (awarded annually by the Lundbeck Foundation) is the most prestigious tribute in neuroscience. The winners in 2021 were Lars Edvinsson, Peter Goadsby, Michael Moskowitz and Jes Olesen. They are the fathers of migraine pathomechanism, which led to revolutionary new treatments. This review summarizes their landmark findings. Methods: Data related to this topic were reviewed from PubMed records published between 1979 and May 2021. Searches were based on preclinical and clinical studies in the covered field. The findings were listed in chronological order. From a therapeutic perspective, only randomized controlled trials and meta-analysis were discussed. Results: The calcitonin gene-related peptide-related pathogenesis of migraine is based on the activation of the trigeminovascular system. The therapeutic triad for migraine is triptans, gepants, and calcitonin gene-related peptide-targeted monoclonal antibodies. Conclusion: In the past 40 years, the systematic work of leading headache scientists has resulted in robust theoretical and therapeutic knowledge in the preclinical and clinical study of migraine.

Background and Objective: Hearing loss is a common audio-vestibular-related neurosensory disability of inner ears, in which patients exhibit clinical symptoms of dizziness, gait unsteadiness, and oscillopsia, at an initial stage. While, if such disorders are untreated for a prolonged duration then the progression of disease into a chronic state significantly decreases GABA level as well as an alteration in the neurotransmission of CNS systems. Hence, to control the progression of disease into a chronic approaches for timely and targeted delivery of the drugs at the site of action in the ear is now attracting the interest of neurologists for effective and safe treatment of such disorders. Among delivery systems, owing to small dimension, better penetration, rate-controlled release, higher bioavailability; nanocarriers are preferred to overcome delivery barriers, improvement in residence time, and enhanced the performance of loaded drugs. Subsequently, these carriers also stabilize encapsulated drugs while also provide an opportunity to modify the surface of carriers to favor guided direction for site-specific targeting. Contrary to this; conventional routes of drug delivery such as oral, intravenous, and intramuscular are poorer in performance because of inadequate blood supply to the inner ear and limited penetration of blood–inner ear barrier. Conclusion: This review summarized novel aspects of non-invasive and biocompatible nanoparticles- based approaches for targeted delivery of drugs into the cochlea of the ear to reduce the rate, and extent of the emergence of any hearing loss mediated neurological disorders.

Background: Sex-related differences in the prevalence and clinical presentation of Obstructive Sleep Apnea Syndrome (OSAS) have been widely documented. The aim of this study was to investigate the influence of patients’ sex on polygraphic parameters with particular attention to sleep autonomic changes in a population of OSAS patients. Methods: Sixty OSAS patients aged 55-65 years (30 men, 30 women) were enrolled. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness with the Epworth Sleepiness Scale (ESS). The presence of respiratory events and autonomic changes during the night was investigated by polygraphy. Results: Similar main cardiovascular risk factors prevalence was observed in both men and women. We observed a significant difference in PSQI (higher in women, p=0.0001) and ESS (higher in men, p=0.004) scores. Snoring (p=0.033), supine AHI (p=0.004), T90 (p=0.021), LO2 (p=0.0001), LF/HF ratio and LF (p=0.0001) were significantly higher in men. Sex differences in PSQI mean score and LF/HF ratio variability were preserved in all the subgroups of OSA severity. Conclusion: The influence of sex in modulating cardiovascular risk is a widely discussed topic. In our study, men showed more severe polygraphic parameters and an increase in LF/HF ratio compared to women. The results of our investigation suggest the relevance of delivering information about the different expressions of OSAS in men and women in order to improve diagnostic skills and in-depth prevention approaches.

Background: In recent years, more and more patients with depression demonstrate suicidal intention and suicidal behavior. Objective: To evaluate the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in treating depression with suicidal ideation. Methods: Eighty-nine depression patients with suicide intention were administrated drugs combined with four weeks of Active rTMS (n=40) or sham (n=49) rTMS treatment. The 24-item Hamilton Depression Rating Scale for Depression (HAMD-24) and Self-rating Idea of Suicide Scale (SIOSS) were used to evaluate suicide risk and depression severity at baseline, weeks 2 and 4. A 25% reduction in HAMD-24 score from baseline was defined as treatment response. More than a 20% reduction in HAMD-24 score from baseline within the first 2 weeks of treatment was defined as an early improvement. Results: No statistical significance was found for baseline sociodemographic and illness characteristics between the two groups (P >0.05). There was a significant difference for HAMD-24 and SIOSS scores between the two groups at weeks 2 and 4. Active rTMS group demonstrated a more significant score reduction compared to the Sham rTMS group at weeks 2 and 4. There was a significantly greater number of patients with early improvement observed in the Active rTMS group compared to those in the Sham rTMS group at weeks 2 (P <0.05). There was a significant difference in responder rates between the two groups at weeks 4 for HAMD-24 scores (P <0.05). Conclusion: rTMS could accelerate the onset time of beneficial treating effects and improve clinical symptoms of depression. During the treatment course, cognitive disorder, sleep disorder, anxiety/ somatization, retardation, and hopelessness symptoms were improved dramatically, and suicidal ideation was reduced.

Background: Epilepsy is a common neurological disorder characterized by abnormal and recurrent neuronal discharges that result in epileptic seizures. The dentate nuclei of the cerebellum receive excitatory input from different brain regions. Purkinje cell loss due to chronic seizures could lead to decreased inhibition of these excitatory neurons, resulting in the activation of apoptotic cascades in the dentate nucleus. Objective: The present study was designed to determine whether there is a presence of apoptosis (either intrinsic or extrinsic) in the dentate nucleus, the final relay of the cerebellar circuit, following kindling-induced seizures. Methods: In order to determine this, seizures were triggered via the amygdaloid kindling model. Following 0, 15, or 45 stimuli, rats were sacrificed, and the cerebellum was extracted. It was posteriorly prepared for the immunohistochemical analysis with cell death biomarkers: TUNEL, Bcl-2, truncated Bid (tBid), Bax, cytochrome C, and cleaved caspase 3 (active form). Our findings reproduce results obtained in other parts of the cerebellum. Results: We found a decrease of Bcl-2 expression, an anti-apoptotic protein, in the dentate nucleus of kindled rats. We also determined the presence of TUNEL-positive neurons, which confirms the presence of apoptosis in the dentate nucleus. We observed the expression of tBid, Bax, as well as cytochrome C and cleaved caspase-3, the main executor caspase of apoptosis. Conclusion: There is a clear activation of both the intrinsic and extrinsic apoptotic pathways in the cells of the dentate nucleus of the cerebellum of rats subjected to amygdaloid kindling.

Background: Pharmacological treatments for mental disorders, such as anxiety and depression, present several limitations and adverse effects. Therefore, new pharmacotherapy with anxiolytic and antidepressant potential is necessary, and the study of compounds capable of interacting with more than one pharmacological target may provide new therapeutic options. Objectives: In this study, we proposed the design, synthesis of a new compound, 2-(4-((1- phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethyl acetate (LQFM192), pharmacological evaluation of its anxiolytic-like and antidepressant-like activities, as well as the possible mechanisms of action involved. Methods: Administration of LQFM192 was carried out prior to the exposure of male Swiss mice to behavioral tests, such as the elevated plus-maze and forced swimming test. The involvement of the serotonergic system was studied by pretreatment with WAY-100635 or p-chlorophenylalanine (PCPA) and the involvement of the benzodiazepine site of the GABAA receptor by pretreatment with flumazenil. Results: The treatment with LQFM192 at doses of 54 and 162 μmol/kg demonstrated anxiolyticlike activity that was blocked by WAY-100635, PCPA, and flumazenil pretreatments. The potential antidepressant-like activity was visualized at the same doses and blocked by WAY-100635 and PCPA. Conclusion: In summary, the anxiolytic-like activity of LQFM192 is mediated by the serotonergic system and the benzodiazepine site of the GABAA receptor, and the antidepressant-like activity through the serotonergic system.

Background: Depression is a group of syndromes characterized by notable and persistent mood disorders, and is one of the most prevalent psychiatric disorders, while the existing treatments have an altered risk-benefit balance. The therapeutic properties of Nigella have been confirmed, suggesting the reliance on phytotherapy. Objectives: The objective of the present paper is to investigate the antidepressive-like effect of Nigella sativa on rats exposed to the Unpredictable Chronic Mild Stress procedure. Methods: Wistar rats were used to investigate the antidepressive-like effect. The stress procedure used in this study combined many stressful conditions. After 6 weeks of treatment, behavioral test (forced swim test) was conducted, and histological changes of the hippocampus were examined. Results: Treatment by nigella and fluoxetine significantly reduced the immobilization time. Histopathological analysis showed that control treatments result in more loosely arranged cells, significant apoptotic neurons characterized by an irregular appearance, and pyknotic hyperchromatic. Conclusion: A preservation of the thickness of the pyramid layer was also observed in the groups treated with nigella and fluoxetine, suggesting that nigella could be used as a treatment or an adjuvant preventing depressive-like disorders.