CNS & neurological disorders drug targets最新文献

Introduction: Glioma, a global concern, a rare but aggressive brain cancer, poses a unique challenge for health scientists. The diagnosis solely depends on Magnetic resonance imaging (MRI) and computed tomography (CT) scans, which are effective but may lead to misinterpretation.

Objective: The present study explores outcomes and develops effective strategies for early detection of glioma. The study also focuses on exploring a comprehensive panel of blood biochemical parameters in this challenging landscape.

Methods: A retrospective study included all adults above 18 years (n=78) diagnosed with Glioma and admitted to King Abdullah Medical City, Mecca. Routine blood biochemistry of whole blood was performed, showing Glioma either IDH mutant or Wild type detected via standard protocol.

Results: Demographic variations categorized by age, gender, nationality, Glioma types, and subtypes, revealing a predominant occurrence in the 51-60 age range. Among gliomas, 33.3% were IDH Mutant, while the remaining 66.7% were Wild type, with Glioblastoma (wild type) being the most prevalent at 64.1%. Creatinine levels (0.60 ± 0.17 mg/dL, p<0.2) and urea levels (4.14 ± 1.55 mg/dL, p<0.05) were lower in females, while alkaline phosphatase (74.90 ± 25.17 uL, p<0.3) and total bilirubin (0.38 ± 0.20 mg/dL, p<0.01) also showed significant differences. Neutrophils were significantly lower in females (4.51 ± 2.31 uL, p<0.01), with elevated lymphocytes (7.46 ± 3.14 uL) and CRP (4.65 ± 7.98 mg/dL, p<0.001). The mutant type had lower levels of ALP (78.46 ± 29.08 uL), AST (22.30 ± 11.06 uL), ALT (30.06 ± 19.22 uL), and GGT (66.15 ± 40.76 uL) compared to the wild type (ALP: 86.98 ± 30.33 uL, AST: 29.98 ± 15.10 uL, ALT: 36.32 ± 20.94 uL, GGT: 83.44 ± 45.91 uL). GGT showed significant variation (p<0.01), with higher neutrophil levels in the wild type (5.69 ± 4.12 uL) compared to the mutant (3.82 ± 2.28 uL). Lymphocytes (4.84 ± 22.94 uL) and CRP (4.29 ± 6.87 mg/dL) were significantly higher (p<0.001) in the wild type.

Discussion: Altered KFL and LFT in Mutant and wild-form Glioma depend upon the gender of patients. Combining these biochemical parameters with existing imaging modalities such as MRI and CT could potentiate the diagnostic accuracy of Glioma, offering a more comprehensive approach to patient care.

Conclusion: The insightful, findings do not replace the crucial role of imaging techniques but could complement them in a multi-model diagnostic approach particularly with altered KFT and LFT in Mutant and wild-form Glioma.

ISG15 is a 15 kDa ubiquitin-like protein that covalently associates with its target proteins by a sequential enzymatic process known as ISGylation. Research on protein ISGylation has increased in recent years, and some studies have suggested that ISG15 is involved in neuroprotection and neurodegeneration mechanisms. This review outlines the current state of research on the implications of ISG15/ISGylation in other neuropathies such as malignant tumors, ataxia telangiectasia, ischemia, depression, and neurodegenerative diseases such as Alzheimer's, Parkinson's diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Based on the studies reported to date, ISG15/ ISGylation promotes the progression of brain tumors such as glioblastoma. Moreover, ISG15/ ISGylation seems to play a dual role in neuropathies, demonstrating a neuroprotective effect when there is acute brain damage, but ISG15/ISGylation is associated with reduced neuroprotection when there is chronic damage, such as in neurodegenerative diseases.

Central Nervous System (CNS) disorders affect millions of people worldwide, with a significant proportion experiencing drug-resistant forms where conventional medications fail to provide adequate seizure control. This abstract delves into recent advancements and innovative therapies aimed at addressing the complex challenge of CNS-related drug-resistant epilepsy (DRE) management. The idea of precision medicine has opened up new avenues for epilepsy treatment. Herbs such as curcumin, ginkgo biloba, panax ginseng, bacopa monnieri, ashwagandha, and rhodiola rosea influence the BDNF pathway through various mechanisms. These include the activation of CREB, inhibition of NF-κB, modulation of neurotransmitters, reduction of oxidative stress, and anti- inflammatory effects. By promoting BDNF expression and activity, these herbs support neuroplasticity, cognitive function, and overall neuronal health. Novel antiepileptic drugs (AEDs) with distinct mechanisms of action demonstrate efficacy in refractory cases where traditional medications falter. Additionally, repurposing existing drugs for antiepileptic purposes presents a cost-effective strategy to broaden therapeutic choices. Cannabidiol (CBD), derived from cannabis herbs, has garnered attention for its anticonvulsant properties, offering a potential adjunctive therapy for refractory seizures. In conclusion, recent advances and innovative therapies represent a multifaceted approach to managing drug-resistant epilepsy. Leveraging precision medicine, neurostimulation technologies, novel pharmaceuticals, and complementary therapies, clinicians can optimize treatment outcomes and improve the life expectancy of patients living with refractory seizures. Genetic testing and biomarker identification now allow for personalized therapeutic approaches tailored to individual patient profiles. Utilizing next-generation sequencing techniques, researchers have elucidated genetic mutations.

Background: Multiple sclerosis (MS) is a persistent autoimmune condition characterized by inflammation and neurodegeneration. The current efficacy of treatments is limited, which has generated interest in developing neuroprotective strategies. Solid lipid nanoparticles (SLNs) and probiotics are potential drug delivery vehicles for targeting the CNS (Central nervous system), regulating immune responses, and supporting neuroprotection in neurological conditions.

Methods: The study investigates how SLNs containing RSG (rosiglitazone) and probiotics can protect the nervous system in cases of MS. We administered toxin EtBr (Ethidium bromide) from day 1 to day 7, later followed by the treatment from day 8 to day 35. During this time interval, various behavioural parameters have been performed. Further, after 35th day, blood plasma of animals was collected to study complete CBC profiling and animals were sacrificed. Then, biochemical and molecular studies, gross morphology of brain sectioning, histopathological evaluation and estimation of fatty acid content in fecal matter were performed.

Results: RSG shows neuroprotective effects by blocking the STAT-3 and mTOR signaling pathways and increasing the production of PPAR-gamma. GW9662, a PPAR-gamma antagonist given at a dose of 2 mg/kg (i.p), was utilized to evaluate the role of PPAR-gamma and to compare the efficacy of RSG and probiotic-loaded SLNs in potentially providing neuroprotection. The relationship between RSG and the STAT-3, mTOR, and PPAR-gamma pathways in MS was confirmed and validated using in-silico analysis. RSG and probiotic-loaded SLNs modulate the complete blood profiling of rats and improve the symptoms of MS. We assessed the diagnostic capabilities of different biological samples such as cerebrospinal fluid, blood plasma, and brain homogenates (specifically from the hippocampus, striatum, cortex, and midbrain) to analyze neurochemical changes linked to neurobehavioral changes in the progression of MS.

Conclusion: The study showed that combining RSG and probiotics in an experimental medication form improved symptoms of MS more effectively than using RSG alone. This improvement is likely due to changes in STAT-3, mTOR, and PPAR-gamma signaling pathways.

Traumatic Brain Injury (TBI) is attributed to a forceful impact on the brain caused by sharp, penetrating bodies, like bullets and any sharp object. Some popular instances like falls, traffic accidents, physical assaults, and athletic injuries frequently cause TBI. TBI is the primary cause of both mortality and disability among young children and adults. Several individuals experience psychiatric problems, including cognitive dysfunction, depression, post-traumatic stress disorder, and anxiety, after primary injury. Behavioral changes post TBI include cognitive deficits and emotional instability (anxiety, depression, and post-traumatic stress disorder). These alterations are linked to neuroinflammatory processes. On the other hand, the direct impact mitigates inflammation insult by the release of pro-inflammatory cytokines, namely IL-1β, IL-6, and TNF-α, exacerbating neuronal injury and contributing to neurodegeneration. During the excitotoxic phase, activation of glutamate subunits like NMDA enhances the influx of Ca²⁺ and leads to mitochondrial metabolic impairment and calpain-mediated cytoskeletal disassembly. TBI pathological insult is also linked to transcriptional response suppression Nrf-2, which plays a critical role against TBI-induced oxidative stress. Activation of NRF-2 enhances the expression of anti-oxidant enzymes, providing neuroprotection. A possible explanation for the elevated levels of NO is that the stimulation of NMDA receptors by glutamate leads to the influx of calcium in the postsynaptic region, activating NOS's constitutive isoforms.

Introduction: Refractory and super-refractory status epilepticus are medical emergencies that must be promptly treated in consideration of their high mortality and morbidity rate. Nevertheless, the available evidence of effective treatment for these conditions is scarce. Among novel antiseizure medications (ASMs), highly purified cannabidiol (hpCBD) has shown noteworthy efficacy in reducing seizures in Lennox-Gastaut syndrome, Dravet syndrome, and Tuberous Sclerosis Complex.

Case presentation: Here, we present two cases of effective use of hpCBD in both refractory and super- refractory status epilepticus. The administration of the nasogastric tube permitted the resolution of status epilepticus without adverse events. At 6-month follow-up, both patients were on hpCBD treatment, which continued to be efficacious for treating seizures.

Conclusion: According to our experience, hpCBD should be taken into consideration as an add-on therapy of RSE and SRSE while also considering the possibility of maintaining this treatment during the follow-up of patients. However, more studies and real-world experiences are needed to better understand its effectiveness in this setting and the interaction with other ASMs.

Introduction: Heme-oxidized iron regulatory protein 2 (IRP2) ubiquitin ligase-1 (HOIL-1) is believed to contribute to the ubiquitination of IRP2, which facilitates the transcription of transferrin receptor 1 (TfR1) while preventing the transcription of ferroportin-1 (FPN-1). Bioinformatics analysis predicts that nadolol (a β-blocker) interacts with the HOIL-1.

Method: The present study is intended to explore whether nadolol suppresses ferroptosis in the brains of rats suffering from ischemic stroke via targeting the HOIL-1/IRP2 pathway. A rat model of ischemic stroke was established by blocking the middle cerebral artery for 2 h plus 24 h reperfusion, and nadolol (2.5 or 5 mg/kg) was given at 1h after reperfusion. HT22 cells were subjected to 12 h of hypoxia, followed by 24 h of reoxygenation for simulating ischemic stroke, and nadolol (0.1 or 0.25 μM) was administered to the culture medium before reoxygenation.

Results: The stroke rats showed evident brain injury (increases in neurological deficit score and infarct volume) and ferroptosis, along with up-regulation of IRP2 and TfR1 while downregulation of HOIL-1 and FPN-1; these phenomena were reversed in the presence of nadolol. In the cultured HT22 cells, hypoxia/reoxygenation-induced LDH release, ferroptosis, and changes in the levels of relevant proteins (IRP2, TfR1, HOIL-1, and FPN-1) were also reversed by nadolol.

Conclusion: In terms of these findings, it is concluded that nadolol can protect the ischemic rats' brains against ferroptosis by targeting the HOIL-1/IRP2 pathway, thereby preventing intracellular iron overload. Thus, nadolol may be a novel indication for treating patients with ischemic stroke.

Inorganic fluoride is widely used in dental practices to treat problems like dental caries and prevent bone-related issues. Exposure to excess amounts of fluoride both through drinking water or other sources impairs vital functions of the body and can prove to be toxic, especially for the central nervous system. Sodium fluoride (NaF) crosses the blood-brain barrier in early developmental stages and causes impairments related to learning and memory, anxiety, decreased locomotor ability, and in some cases, depression-like behaviour, especially in children. Major mechanisms involved in this toxicity include reduction in levels of nicotinic and muscarinic receptors, autophagy, and apoptosis in neurons, decreased glucose consumption, inhibition of enzymes involved in the generation of energy and transmission of the synapse, mitochondrial dysfunction, and increased oxidative stress leading to inflammation and neuronal cell death. Out of all these, an increase in oxidative stress was reported to be one of the main mechanisms of fluoride-induced neurotoxicity. Based on these inferences, various natural compounds having antioxidant properties, like curcumin, aloe vera, quercetin, epigallocatechin gallate, etc. have been studied for their protective role in sodium fluoride-induced neurotoxicity. Involvement of other pathways like Nrf2/Keap pathways, SIRT3, etc., have warranted a need for further detailed study to identify other potential therapeutic targets like AMPK to prevent/treat fluoride-induced neurotoxicity. The present review captures fluoride, its role in neurodevelopment, and mechanisms & pathways involved by which fluoride can hurt neurodevelopment & how AMPK can be a possible therapeutic target.

Chemotherapy-induced pain is one of the major challenges that hamper the patient's quality of life. Several cases of insufficient pain management were reported globally, especially in the case of patients who do not respond well to conventional pain management regimes and opioid analgesics. Additionally, conventional pain management has several shortcomings, and evidence suggests that cannabidiol has the potential to overcome those shortcomings. Cannabidiol (CBD) is a non-psychoactive compound of the Cannabis plant that shows an effective outcome in chemotherapy- induced pain as well as in cancer treatment, as it possesses anti-inflammatory and analgesic properties. The mechanism of pain and its management by cannabidiol, with all possible evidence, is well summarised in the paper. This article concludes the types of pain experienced by cancer patients, the effectiveness of CBD in the management of pain, and challenges faced by patients after using Cannabidiol with various case studies. Later, antitumor efficacy studies of CBD were disclosed, and its various types of formulations and nano-formulations were summarized in the paper. Overall, the paper establishes the role of cannabidiol in Chemotherapy-induced pain.

Opioid addiction is a condition of the central nervous system that occurs as a result of using opiate-based substances, which can be either natural or synthetic chemicals. These have effects identical to those of morphine and work by interacting with opioid receptors such as morphine, heroin, opium, buprenorphine, and Oxycontin. Dopamine has been suggested to play a role in the mechanisms linked to opioid addiction. Additionally, neurotransmitters such as serotonin, norepinephrine, glutamate, and GABA may also have a significant impact. These processes play a critical role in the formation of brain circuits that are involved in the development of addictive behavior. The PI3K-Akt-mTOR pathway is widely recognized as an essential regulator of the effects induced by neurotransmitters on synaptic plasticity, protein synthesis, and cellular responses. This interplay has considerable importance in the development and persistence of opioid addiction, impacting several domains, including reward processing, stress reactivity, and brain plasticity. The understanding of these neurochemical modifications provides vital insights into the underlying mechanisms of addiction and presents potential pathways for treatments. The review enlisted the clinical trials of different types of opioid addiction or dependence. The review offers a succinct summary of many studies that establish a correlation between the PI3K/Akt-mTOR signaling pathway and various receptors implicated in multiple forms of opioid-related dependency.