CNS & neurological disorders drug targets最新文献

Aims: Neuronal disorders have affected more than 15% of the world's population, signifying the importance of continued design and development of drugs that can cross the Blood-Brain Barrier (BBB).

Background: BBB limits the permeability of external compounds by 98% to maintain and regulate brain homeostasis. Hence, BBB permeability prediction is vital to predict the activity of a drug-like substance.

Objective: Here, we report about developing BBBper (Blood-Brain Barrier permeability prediction) using machine learning tool.

Method: A supervised machine learning-based online tool, based on physicochemical parameters to predict the BBB permeability of given chemical compounds was developed. The user-end webpage was developed in HTML and linked with back-end server by a python script to run user queries and results.

Result: BBBper uses a random forest algorithm at the back end, showing 97% accuracy on the external dataset, compared to 70-92% accuracy of currently available web-based BBB permeability prediction tools.

Conclusion: The BBBper web tool is freely available at http://bbbper.mdu.ac.in.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder marked by the deterioration of dopamine-producing neurons, resulting in motor impairments like tremors and rigidity. While the precise cause remains elusive, genetic and environmental factors are implicated. Mitochondrial dysfunction, oxidative stress, and protein misfolding contribute to the disease's pathology. Current therapeutics primarily aim at symptom alleviation, employing dopamine replacement and deep brain stimulation. However, the quest for disease-modifying treatments persists. Ongoing clinical trials explore novel approaches, such as neuroprotective agents and gene therapies, reflecting the evolving PD research landscape. This review provides a comprehensive overview of PD, covering its basics, causal factors, major pathways, existing treatments, and a nuanced exploration of ongoing clinical trials. As the scientific community strives to unravel PD's complexities, this review offers insights into the multifaceted strategies pursued for a better understanding and enhanced management of this debilitating condition.

Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.

Parkinson's Disease (PD) is a progressive disorder worldwide and its etiology remains unidentified. Over the last few decades, animal models of PD have been extensively utilized to explore the development and mechanisms of this neurodegenerative condition. Toxic and transgenic animal models for PD possess unique characteristics and constraints, necessitating careful consideration when selecting the appropriate model for research purposes. Animal models have played a significant role in uncovering the causes and development of PD, including its cellular and molecular processes. These models suggest that the disorder arises from intricate interplays between genetic predispositions and environmental influences. Every model possesses its unique set of strengths and weaknesses. This review provides a critical examination of animal models for PD and compares them with the features observed in the human manifestation of the disease.

Background and objective: The brain α7 nicotinic acetylcholine receptor (α7 nAChR) has a critical role in the pathophysiology of Major Depressive Disorder (MDD) involving neuroinflammation. The α7 nAChR stimulation has been shown to modulate the anti-inflammatory effects of nuclear peroxisome proliferator-activated receptor-α (PPAR-α) via its endogenous ligands in the brain. The present study determined the effects of α7 nAChR modulator PNU120596 on PPAR-α, an inhibitor of κB (IκB) and nuclear factor-κB (NF-κB) expression and interleukin-1β (IL-1β) level in the hippocampus and prefrontal cortex (PFC) in an inflammatory mouse model of MDD induced by lipopolysaccharide (LPS). We also evaluated the combined effects of PNU120596 and GW6471, a PPAR-α antagonist, on depressive-like and cognitive deficit-like behaviors in mice.

Materials and methods: Male C57BL/6J mice were treated with PNU120596, followed by systemic LPS (1 mg/kg, i.p.) administration. The effects of PNU120596 on the mRNA expression of PPAR-α and IκB were assessed in the hippocampus and PFC using qRT-PCR following LPS administration. Similarly, the effects of PNU120596 on the immunoreactivity of PPAR-α and NF-κB were measured in the hippocampus and PFC using an immunofluorescence assay. Furthermore, the effects of PNU120596 on pro-inflammatory cytokine IL-1β levels were measured in the hippocampus and PFC using ELISA. The combined effects of PNU120596 and GW6471 were also assessed against LPS-induced depressive-like and cognitive deficit-like behaviors using the Tail Suspension Test (TST), Forced Swim Test (FST), and Y-maze test.

Results: PNU120596 (4 mg/kg) significantly prevented LPS-induced dysregulation of PPAR-α, IκB, p-NF-κB p65, and IL-1β in the hippocampus and PFC. Pretreatment with PNU120596 showed significant antidepressant-like effects by reducing immobility time in the TST and FST. Similarly, pretreatment with PNU120596 significantly reduced cognitive deficit-like behavior in the Y-maze test. The antidepressant and pro-cognitive-like effects of PNU120596 were reversed by PPAR-α antagonist GW6471 (2 mg/kg).

Conclusion: These results suggest that PNU120596 prevented LPS-induced MDD and cognitivelike behavior by regulating α7 nAChR/PPAR-α signaling pathway in the hippocampus and PFC.

Repurposing drugs (DR) has become a viable approach to hasten the search for cures for neurodegenerative diseases (NDs). This review examines different off-target and on-target drug discovery techniques and how they might be used to find possible treatments for non-diagnostic depressions. Off-target strategies look at the known or unknown side effects of currently approved drugs for repositioning, whereas on-target strategies connect disease pathways to targets that can be treated with drugs. The review highlights the potential of experimental and computational methodologies, such as machine learning, proteomic techniques, network and genomics-based approaches, and in silico screening, in uncovering new drug-disease correlations. It also looks at difficulties and failed attempts at drug repurposing for NDs, highlighting the necessity of exact and standardised procedures to increase success rates. This review's objectives are to address the purpose of drug repurposing in human disorders, particularly neurological diseases, and to provide an overview of repurposing candidates that are presently undergoing clinical trials for neurological conditions, along with any possible causes and early findings. We then include a list of drug repurposing strategies, restrictions, and difficulties for upcoming research.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes atrophy of brain cells, leading to their death, and has become a leading cause of death in aging populations worldwide. AD is characterized by β-amyloid (Aβ) deposition and tau phosphorylation in neural tissues, but the precise pathophysiology of the disease is still obscure. Autophagy is an evolutionarily targeted mechanism that is necessary for the elimination of neuronal and glial misfolded proteins as well as proteins. It also plays an essential role in synaptic plasticity. The aberrant autophagy primarily influences the process of aging and neurodegeneration. Autophagy significantly influences how Aβ and tau function physiologically, therefore, atypical autophagy is expected to perform an important role in Aβ deposition and tau phosphorylation characteristic in the development of AD. Bioactive phytoconstituents could majorly contribute as a natural yet effective alternative approach to slow down the progression of neurodegeneration and promote the active aging process in elderly patients. Over the recent years, it is well evidenced that different secondary metabolites including polyphenols, alkaloids, terpenes, and phenols exhibited neuroprotective effects, and attenuated brain damage, and cognitive impairment in vitro as well as in vivo. Additionally, the underlying mechanism of action shared by them is the regulation of competent autophagy via the removal of aggregated protein and mitochondrial dysfunction. The present article is structured as a reference for researchers keen to investigate and assess the new natural compound-mediated therapeutic approach for AD treatment through the modulation of autophagy.

The prevalence of neurodegenerative diseases has increased with longer life expectancies, necessitating the exploration of novel neuroprotective agents. Tangeretin, a polymethoxylated flavone derived from citrus fruits, has gathered attention for its potential therapeutic effects. This review highlights the neuroprotective properties of tangeretin via its antioxidant and anti-inflammatory mechanisms. Tangeretin demonstrates efficacy in mitigating oxidative stress, neuroinflammation, and neuronal damage across various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, and epilepsy. It shows promise in ameliorating cognitive deficits and memory impairments associated with these diseases. Moreover, tangeretin modulates multiple signalling pathways and protects against neuronal apoptosis, underscoring its potential as a therapeutic agent.

The triptans class of pharmaceuticals, which was created to treat acute migraine, is made up of indole-containing drugs that bind to a subset (1B/1D) of 5-hydroxytryptamine receptors and are agonists of serotonin receptors. At the moment, naratriptan, eletriptan, zolmitriptan, rizatriptan, almotriptan, and frovatriptan are the seven types of triptans available on the market. Among these are the FDA-approved triptans, Zolmitriptan and Sumatriptan, which are selective serotonin (5-hydroxytryptamine) agonists. Zolmitriptan, a synthetic tryptamine derivative and a well-known member of the triptan family, is available as an orally disintegrating tablet, nasal spray, and tablet. There are melt formulations of rizatriptan and zolmitriptan available on the market that are easier to use and absorb, comparable to regular pills. Recently, the FDA approved zolmitriptan, a medication with tolerability comparable to sumatriptan. Whereas zolmitriptan is only available as an oral melt or tablet, sumatriptan is available as a nasal spray, oral preparation, or self-injectable kit. The only known antimigraine drugs that were widely utilized before the triptan period were ergotamine and dihydroergotamine. However, zolmitriptan binds to plasma proteins only 25% of the time because of significant first-pass degradation. Researchers have looked into fresh ideas for solving this issue and innovations to overcome its pharmacokinetic difficulties. This article emphasizes the role of zolmitriptan in the treatment of migraines, highlighting its pharmacological properties, production, metabolism, and structural features.

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.