CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 19, Issue 4, 2020

Lumateperone (ITI-007) is a tosylate salt with binding affinities to receptors implicated in the therapeutic actions of antipsychotic medications, including the serotonin 5HT2A receptors, dopamine D2 and D1 receptors and the serotonin transporter. It has a unique mechanism of action because it simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, implicated in serious mental illness. It can be considered a multi-target-directed ligand and a multifunctional modulator of serotoninergic system with possible precognitive, antipsychotic, antidepressant and anxiolytic properties. Lumateperone has been investigated as a novel agent for the treatment of schizophrenia, but it represents a new potential option for other psychiatric and neurological diseases, such as behavioural symptoms of dementia or Alzheimer’s disease, sleep disturbances, bipolar depression. Besides, it has demonstrated a favourable safety profile without significant extrapyramidal side effects, hyperprolactinemia or changes in cardiometabolic or endocrine factors versus placebo. Additional studies are warranted to confirm and examine the benefit of lumateperone and possible therapeutic targets. This paper is a comprehensive and thorough summary of the most important findings and potential future role of this particular compound in personalized treatments.

Stroke is a complex disease caused by genetic and environmental factors, and its etiological mechanism has not been fully clarified yet, which brings great challenges to its effective prevention and treatment. MAPK signaling pathway regulates gene expression of eukaryotic cells and basic cellular processes such as cell proliferation, differentiation, migration, metabolism and apoptosis, which are considered as therapeutic targets for many diseases. Up to now, mounting evidence has shown that MAPK signaling pathway is involved in the pathogenesis and development of ischemic stroke. However, the upstream kinase and downstream kinase of MAPK signaling pathway are complex and the influencing factors are numerous, the exact role of MAPK signaling pathway in the pathogenesis of ischemic stroke has not been fully elucidated. MAPK signaling molecules in different cell types in the brain respond variously after stroke injury, therefore, the present review article is committed to summarizing the pathological process of different cell types participating in stroke, discussed the mechanism of MAPK participating in stroke. We further elucidated that MAPK signaling pathway molecules can be used as therapeutic targets for stroke, thus promoting the prevention and treatment of stroke.

Neurological diseases expose individuals to a higher risk of suicidal ideation and suicidal behavior, including completed suicides and suicide attempts. They also represent a paradigmatic arena to study the etiopathogenic mechanisms underlying suicidality because they are emblematic of the heterogeneity and complexity of mutual interrelationships characterizing this issue. On the one hand, neurological diseases imply strictly biological impairments that are postulated to be the basis of vulnerability to suicide or result in the need for treatments for which a suicidal risk has been hypothesized. On the other hand, they question some subjective experiences of neurological patients, up to near existential positions. Often, in fact, they are accompanied by severe hopelessness. The latter may originate in, particularly for the most severe neurological diseases, the absence of curative treatments, unpredictable disease progression that leads to acute relapses or chronicity, a decrease in autonomy or selfidentity, progressive social isolation, a sense of becoming useless, and perception of feeling stigmatized. This may ultimately cause a slip into experiencing an absurd condition. At the confluence of neurobiology and hopelessness, frequent psychiatric comorbidities may play a primary role. To conclude, neurological patients require special attention from clinicians in form of openly verbalizing and exploring the suicidal thematic, inquiring about protective and risk factors, and promptly initiating both a psychopharmacological treatment and, where possible, psychological support.

Background: Mammalian central neurons regulate their intracellular pH (pHi) strongly and even slight pHi-fluctuations can influence inter-/intracellular signaling, synaptic plasticity and excitability. Objective: For the first time, we investigated topiramate´s (TPM) influence on pHi-behavior of human central neurons representing a promising target for anticonvulsants and antimigraine drugs. Methods: In slice-preparations of tissue resected from the middle temporal gyrus of five adults with intractable temporal lobe epilepsy, BCECF-AM-loaded neocortical pyramidal-cells were investigated by fluorometry. The pHi-regulation was estimated by using the recovery-slope from intracellular acidification after an Ammonium-Prepulse (APP). Results: Among 17 pyramidal neurons exposed to 50 μM TPM, seven (41.24%) responded with an altered resting-pHi (7.02±0.12), i.e., acidification of 0.01-0.03 pH-units. The more alkaline the neurons, the greater the TPM-related acidifications (r=0.7, p=0.001, n=17). The recovery from APPacidification was significantly slowed under TPM (p<0.001, n=5). Further experiments using nominal bicarbonate-free (n=2) and chloride-free (n=2) conditions pointed to a modulation of the HCO3^--driven pHi-regulation by TPM, favoring a stimulation of the passive Cl^-/HCO3^--antiporter (CBT) - an acid-loader predominantly in more alkaline neurons. Conclusion: TPM modulated the bicarbonate-driven pHi-regulation, just as previously described in adult guinea-pig hippocampal neurons. We discussed the significance of the resulting subtle acidifications for beneficial antiepileptic, antimigraine and neuroprotective effects as well as for unwanted cognitive deficits.

Background: Studies have found that autophagy could promote the clearance of Aβ. To promote and maintain the occurrence of autophagy in Alzheimer's Disease (AD) might be a potential way to reduce neuronal loss and improve the learning and memory of AD. Objective: To investigate the possible mechanisms of Yishen Huazhuo Decoction (YHD) against AD model. Methods: Forty 7-month-old male SAMP8 mice were randomly divided into model (P8) group and YHD group, 20 in each group, with 20 SAMR1 mice as control (R1) group. All mice were intragastrically administered for 4 weeks, YHD at the dosage of 6.24g/kg for YHD group, and distilled water for P8 group and R1 group. Morris Water Maze (MWM) test, Nissl’s staining, TEM, TUNEL staining, immunofluorescence double staining, and western blot analysis were applied to learning and memory, structure and ultrastructure of neurons, autophagosome, apoptosis index, Aβ, LAMP1, and autophagy related proteins. Results: The escape latency time of YHD group was significantly shorter on the 4th and 5th day during MWM test than those in P8 group (P=0.011, 0.008<0.05), and the number of crossing platform in YHD group increased significantly (P=0.02<0.05). Nissl’s staining showed that the number of neurons in YHD group increased significantly (P<0.0001). TEM showed in YHD group that the nucleus of neurons was slightly irregular, with slightly reduced organelles, partially fused and blurred cristae and membrane of mitochondria. The apoptosis index of YHD group showed a decreasing trend, without statistically significant difference (P=0.093>0.05), while Caspase3 expression in YHD group was significantly lower (P=0.044<0.05). YHD could promote the clearance of Aβ1-42 protein, improve the expression of Beclin-1 and p-Bcl2 proteins, reduce mTOR and p62 proteins. Conclusion: YHD could induce autophagy initiation, increase the formation of autophagosomes and autolysosome, promote the degradation of autophagy substrates, thereby regulating autophagy, and promoting the clearance of Aβ1-42 to improve memory impairment in SAMP8 mice.

Introduction: Lisdexamfetamine (LDX) is a drug used to treat ADHD/impulsive patients. Impulsivity is known to affect inhibitory, emotional and cognitive function. On the other hand, smell and odor processing are known to be affected by neurological disorders, as they are modulators of addictive and impulsive behaviors specifically. We hypothesize that, after LDX ingestion, inhibitory pathways of the brain would change, and complementary behavioral regulation mechanisms would appear to regulate decision-making and impulsivity. Methods: 20 children were studied in an aleatory crossover study. Imaging of BOLD-fMRI activity, elicited by olfactory stimulation in impulsive children, was performed after either LDX or placebo ingestion. Results: Findings showed that all subjects who underwent odor stimulation presented activations of similar intensities in the olfactory centers of the brain. This contrasted with inhibitory regions of the brain such as the cingulate cortex and frontal lobe regions, which demonstrated changed activity patterns and intensities. While some differences between the placebo and medicated states were found in motor areas, precuneus, cuneus, calcarine, supramarginal, cerebellum and posterior cingulate cortex, the main changes were found in frontal, temporal and parietal cortices. When comparing olfactory cues separately, pleasant food smells like chocolate seemed not to present large differences between the medicated and placebo scenarios, when compared to non-food-related smells. Conclusion: It was demonstrated that LDX, first, altered the inhibitory pathways of the brain, secondly it increased activity in several brain regions which were not activated by smell in drug-naïve patients, and thirdly, it facilitated a complementary behavioral regulation mechanism, run by the cerebellum, which regulated decision-making and impulsivity in motor and frontal structures.

Background: Due to the recent development of non-invasive examinations, more asymptomatic patients with Moyamoya Disease (MMD) have been diagnosed than ever. However, its underlying molecular mechanisms and clinical intervention guidelines are all still obscure. Methods: Microarray was used to explore those differentially expressed mRNAs and lncRNAs in peripheral neutrophils of asymptomatic MMD patients. Then enrichment analyses based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for those differentially expressed mRNAs and lncRNA associated mRNAs were performed for underlying molecular mechanisms. Results: Here, we identified a total of 2824 differentially expressed lncRNAs and 522 differentially expressed mRNAs (fold change > 2 and P<0.05) in peripheral neutrophils of asymptomatic MMD patients, compared with healthy controls. Then enrichment analyses based on GO and KEGG showed that the neighboring protein-coding mRNAs of those up-regulated and down-regulated lncRNAs were mainly involved in distinct metabolic processes respectively, which may act as a complementary response to insufficient blood supplies in MMD. Further enrichment analyses of those differentially expressed mRNAs preferentially listed essential physiological processes such as peptide cross-linking, chromatin assembly among others. Moreover, altered mRNAs also revealed to be enriched in renin secretion, platelet activation, inflammation and others. Conclusion: We demonstrated for the first time that metabolic adjustments by dysregulated lncRNAs in peripheral neutrophils might partially account for the complete compensation of asymptomatic MMD patients. In addition, more attention should be paid on renin secretion and platelet activation in order to better understand the pathogenesis and guide clinical intervention for asymptomatic MMDs.