Drug induced neurological disorders

Ataxia Telangiectasia (AT) and Aicardi Goutières syndrome (AGS) are inherited disorders of immunity with prevalent neurological phenotype. Available treatments are only partially effective and the prognosis is poor. Induced pluripotent stem cells (iPSCs) are obtained by reprogramming patient somatic cells preserving the donor individual genetic heritage and creating patient specific disease models, useful to investigate pathogenesis, drug effects and to develop precision therapies. The aim is to investigate the cytotoxicity of a panel of immunomodulators using iPSCs of patients with AT or different forms of AGS (AGS1, AGS2 and AGS7)...

Quadripulse stimulation (QPS) is a newly developed stimulation method to induce neural plasticity in humans. One stimulation burst consisting of four monophasic pulses is given every 5 s for 30 min. A total of 360 bursts (1440 pulses) are given in one session. Short-interval QPS potentiates the target cortical excitability and long-interval QPS depresses it. QPS at an inter-pulse interval of 5 ms (QPS5) induces long-term potentiation (LTP)-like effects most efficiently and QPS50 induces long-term depression (LTD)-like effects most effectively in the primary motor cortex...

Kelch-like ECH-associated protein (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) protein-protein interaction has become an important drug target for the treatment of Alzheimer's disease. In this study, we found a novel piperine derivative (HJ22) synthesized by our group with great ability to bind to Keap-1 and activate Keap1-Nrf2-ARE signaling pathway in vitro, driving us to investigate the beneficial effects of HJ22 on ibotenic acid (IBO)-induced neurological disorders in rats and underlying mechanisms...

Background: Levosulpiride (LS) is a prokinetic drug increasingly used for the gastric motility disorders. Despite its common use for the gastric motility disorder, the tendency to cause parkinsonism and acute dystonias are under-recognized as the major adverse effects. This study was aimed to evaluate the adverse effects of this drug in patients attending neurology clinics. Methods: Patients presenting with new-onset extrapyramidal symptoms with respect to LS therapy were selected for the study...

Essential tremor is one of the most common neurological disorders, however, it is not sufficiently controlled with currently available pharmacotherapy. Our recent study has shown that pramipexole, a drug efficient in inhibiting parkinsonian tremor, reduced the harmaline-induced tremor in rats, generally accepted to be a model of essential tremor. The aim of the present study was to investigate brain targets for the tremorolytic effect of pramipexole by determination of the early activity-dependent gene zif-268 mRNA expression...

The tendency to engage in addictive behaviors has long been tied to the actions of the dopamine system. Early theories were based on the fact that all addictive drugs and behaviors (such as gambling) increase dopamine levels in the striatum, and the evidence that dopamine signaled reward or reward prediction error. However, with a changing emphasis of addiction away from purely pharmacological models that emphasize tolerance and withdrawal, towards one of behavioral dyscontrol, is there still a place for abnormal dopamine signaling in addiction? Here we recast the dopamine theory of addiction based on the idea that tonic dopamine may index a continuous phenotype that goes from apathy to impulsivity and compulsivity...

Epilepsy is a chronic neurological disease characterized by excessive neuronal activity leading to seizure; about 30% of affected patients suffer from the refractory and pharmacoresistant form of the disease. The anticonvulsant drugs currently used for seizure control are associated with adverse reactions, making it important to search for more effective drugs with fewer adverse reactions. There is increasing evidence that endocannabinoids can pharmacologically modulate action against seizure and antiepileptic disorders...

There are virtually no clinically available neuroprotective drugs for the treatment of acute and chronic neurological disorders, hence there is an urgent need for the development of new neuroprotective molecules. Cationic arginine-rich peptides (CARPs) are an expanding and relatively novel class of compounds, which possess intrinsic neuroprotective properties. Intriguingly, CARPs possess a combination of biological properties unprecedented for a neuroprotective agent including the ability to traverse cell membranes and enter the CNS, antagonize calcium influx, target mitochondria, stabilize proteins, inhibit proteolytic enzymes, induce pro-survival signaling, scavenge toxic molecules, and reduce oxidative stress as well as, having a range of anti-inflammatory, analgesic, anti-microbial, and anti-cancer actions...

NMDA receptors (NMDARs) are glutamate-gated ion channels that contribute to nearly all brain processes. Not surprisingly then, genetic variations in the genes encoding NMDAR subunits can be associated with neurodevelopmental, neurological, and psychiatric disorders. These disease-associated variants (DAVs) present challenges, such as defining how DAV-induced alterations in receptor function contribute to disease progression and how to treat the affected individual clinically. As a starting point to overcome these challenges, we need to refine our understanding of the complexity of NMDAR structure-function...

Human induced pluripotent stem cells (hiPSCs) have transformed conventional drug discovery pathways in recent years. In particular, recent advances in hiPSC biology, including organoid technologies, have highlighted a new potential for neural drug discovery with clear advantages over the use of primary tissues. This is important considering the financial and social burden of neurological health care worldwide, directly impacting the life expectancy of many populations. Patient-derived iPSCs-neurons are invaluable tools for novel drug-screening and precision medicine approaches directly aimed at reducing the burden imposed by the increasing prevalence of neurological disorders in an aging population...

Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis. Here we demonstrated that post-ischemic treatment with ciclopirox olamine (CPX), a potent antifungal clinical drug, alleviated brain infarction, neurological deficits and brain edema in a classic rat model of ischemic stroke. Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect, which can be further enhanced by multiple doses administration of CPX. CPX also effectively reversed ischemia-induced neuronal loss, glial activation as well as blood-brain barrier (BBB) damage...

Objectives: Neuropathic pain is a prevalent and debilitating neurological disorder. Ample evidence indicates that microglial cells and inflammatory cytokines are involved in the pathogenesis of neuropathic pain. Alpha-terpineol is a monoterpenoid alcohol with inhibitory effect on inflammatory cytokines. The main purpose of this study was to evaluate the effect of α-terpineol on neuropathic pain in rats. Materials and Methods: Chronic constriction injury (CCI) model was utilized to induce neuropathic pain in male Wistar rats...

BACKGROUND: 5-Fluorouracil (5-FU)-induced hyperammonaemic encephalopathy is a rare but serious 5-FU adverse drug reaction (ADR). Given the growing number of cancers treated with 5-FU and the paucity of data regarding this ADR, we performed a retrospective national survey to better characterise 5-FU-induced hyperammonaemic encephalopathy. PATIENTS AND METHODS: Since inception of the French pharmacovigilance database, we identified all patients who experienced 5-FU-induced hyperammonaemic encephalopathy...

Epilepsy is a chronic neurological disorder generally defined to be caused by excessive neuronal activity. Thus, excessive neuronal activity is the main target of the currently used antiepileptic drugs (AEDs). However, as many as 30% of epileptic patients show drug resistance to currently available AEDs, which suggests that epilepsy should be attributed not only to neuronal cells but also to other brain cells, such as glial cells and vascular cells. Astrocytes, pericytes, and endothelial cells in particular comprise the blood-brain barrier (BBB), which tightly regulates the exchange of substances between the brain parenchyma and the circulating blood...

Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain's reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABAB R2 subunit, promotes internalization of the GABAB receptor and leads to smaller GABAB R-activated G protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons...

Pulsed low-intensity focused ultrasound (PLIFUS) has shown promise in inducing neuromodulation in several animal and human studies. Therefore, it is of clinical interest to develop experimental platforms to test repetitive PLIFUS as a therapeutic modality in humans with neurologic disorders. In the study described here, our aim was to develop a laboratory-built experimental device platform intended to deliver repetitive PLIFUS across the hippocampus in seizure onset zones of patients with drug-resistant temporal lobe epilepsy...

Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders...

Pyrroloquinoline quinone (PQQ) and its esterified derivative, PQQ ester (PQQE), have potential to treat or diagnose neurological and psychological disorders. However, their neurotoxicity remains unclear. To provide reference data for the brain targeting drug delivery techniques, the cytotoxic effects of PQQ and PQQE were examined in primary mouse cortical neurons. The results indicated that both PQQ and PQQE decreased neuron viability, reduced intracellular ATP level and disrupted the mitochondrial membrane potential in a concentration- and time-dependent manner, while PQQ was less potent than PQQE...

Epilepsy is a common cause of serious cognitive disorders and is known to have impact on patients' memory and executive functions. Therefore, the development of antiepileptic drugs for the improvement of spatial learning and memory in patients with epileptic cognitive dysfunction is important. In the present work, we systematically predicted and analyzed the potential effects of Ginkgo terpene trilactones (GTTL) on cognition and pathologic changes utilizing in silico and in vivo approaches. Based on our established chemogenomics knowledgebase, we first conducted the network systems pharmacology analysis to predict that ginkgolide A/B/C may target 5-HT 1A, 5-HT 1B, and 5-HT 2B...

Spinal cord injury (SCI) induces pathological and inflammatory responses that create an inhibitory environment at the site of trauma, resulting in axonal degeneration and functional disability. Combination therapies targeting multiple aspects of the injury, will likely be more effective than single therapies to facilitate tissue regeneration after SCI. In this study, we designed a dual-delivery system consisting of a neuroprotective drug, minocycline hydrochloride (MH), and a neuroregenerative drug, paclitaxel (PTX), to enhance tissue regeneration in a rat hemisection model of SCI...