Current Neuropharmacology - Volume 22, Issue 6, 2024

Neurodegenerative disorders (NDDs) are multifaceted complex disorders that have put a great health and economic burden around the globe nowadays. The multi-factorial nature of NDDs has presented a great challenge in drug discovery and continuous efforts are in progress in search of suitable therapeutic candidates. Nature has a great wealth of active principles in its lap that has cured the human population since ancient times. Natural products have revealed several benefits over conventional synthetic medications and scientists have shifted their vision towards exploring the therapeutic potentials of natural products in the past few years. The structural mimicking of natural compounds to endogenous ligands has presented them as a potential therapeutic candidate to prevent the development of NDDs. In the presented review, authors have summarized demographical facts about various NDDs including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and various types of sclerosis in the brain. The significant findings of new active principles of natural origin along with their therapeutic potentials on NDDs have been included. Also, a description of clinical trials and patents on natural products has been enlisted in this compilation. Although natural products have shown promising success in drug discovery against NDDs, still their use is associated with several ethical issues which need to be solved in the upcoming time.

Meningeal lymphatic vessels (MLVs) are essential for the drainage of cerebrospinal fluid, macromolecules, and immune cells in the central nervous system. They play critical roles in modulating neuroinflammation in neurodegenerative diseases. Dysfunctional MLVs have been demonstrated to increase neuroinflammation by horizontally blocking the drainage of neurotoxic proteins to the peripheral lymph nodes. Conversely, MLVs protect against neuroinflammation by preventing immune cells from becoming fully encephalitogenic. Furthermore, evidence suggests that neuroinflammation affects the structure and function of MLVs, causing vascular anomalies and angiogenesis. Although this field is still in its infancy, the strong link between MLVs and neuroinflammation has emerged as a potential target for slowing the progression of neurodegenerative diseases. This review provides a brief history of the discovery of MLVs, introduces in vivo and in vitro MLV models, highlights the molecular mechanisms through which MLVs contribute to and protect against neuroinflammation, and discusses the potential impact of neuroinflammation on MLVs, focusing on recent progress in neurodegenerative diseases.

While symptomatic pharmacological therapy remains the main therapeutic strategy for Parkinson’s disease (PD), over the last two decades, surgical approaches have become more commonly used to control levodopa-induced motor complications and dopamine-resistant and non-motor symptoms of PD. In this paper, we discuss old and new surgical treatments for PD and the many technological innovations in this field. We have initially reviewed the relevant surgical anatomy as well as the pathological signaling considered to be the underlying cause of specific symptoms of PD. Subsequently, early attempts at surgical symptom control will be briefly reviewed. As the most well-known surgical intervention for PD is deep brain stimulation, this subject is discussed at length. As deciding on whether a patient stands to benefit from DBS can be quite difficult, the different proposed paradigms for precisely this are covered. Following this, the evidence regarding different targets, especially the subthalamic nucleus and internal globus pallidus, is reviewed as well as the evidence for newer proposed targets for specific symptoms. Due to the rapidly expanding nature of knowledge and technological capabilities, some of these new and potential future capabilities are given consideration in terms of their current and future use. Following this, we have reviewed newer treatment modalities, especially magnetic resonance-guided focused ultrasound and other potential surgical therapies, such as spinal cord stimulation for gait symptoms and others. As mentioned, the field of surgical alleviation of symptoms of PD is undergoing a rapid expansion, and this review provides a general overview of the current status and future directions in the field.

Physical exercise is considered a promising medication-free and cost-effective adjunct treatment for substance use disorders (SUD). Nevertheless, evidence regarding the effectiveness of these interventions is currently limited, thereby signaling the need to better understand the mechanisms underlying their impact on SUD, in order to reframe and optimize them. Here we advance that physical exercise could be re-conceptualized as an “interoception booster”, namely as a way to help people with SUD to better decode and interpret bodily-related signals associated with transient states of homeostatic imbalances that usually trigger consumption. We first discuss how mismatches between current and desired bodily states influence the formation of reward-seeking states in SUD, in light of the insular cortex brain networks. Next, we detail effort perception during physical exercise and discuss how it can be used as a relevant framework for re-dynamizing interoception in SUD. We conclude by providing perspectives and methodological considerations for applying the proposed approach to mixed-design neurocognitive research on SUD.

MicroRNA-206 (miR-206) is a microRNA that is involved in many human diseases, such as myasthenia gravis, osteoarthritis, depression, cancers, etc. Both inhibition effects and progression roles of miR-206 have been reported for the past few years. High expression of miR-206 was observed in patients with osteoarthritis, gastric cancer and epithelial ovarian cancer compared to normal people. The study also showed that miR-206 promotes cancer progression in breast cancer patients and avascular necrosis of the femoral head. Meanwhile, several studies have shown that expression levels of miR-206 were down-regulated in laryngeal carcinoma cell multiplication, as well as in hepatocellular carcinoma, non-small lung cancer and infantile hemangioma. Moreover, miR-206 was up-regulated in the mild stage of amyotrophic lateral sclerosis patients and then down-regulated in the moderate and severe stages, indicating that miR-206 has the double effects of starting and aggravating the disease. In neuropsychiatric disorders, such as depression, miR-206 also plays an important role in the progression of the disease; the level of miR-206 is most highly expressed in the brains of patients with depression. In the current review, we summarize the role of miR-206 in various diseases, and miR-206 may be developed as a new biomarker for diagnosing diseases in the near future.

Neurodegenerative disease (ND) incidence has recently increased due to improved life expectancy. Alzheimer's (AD) or Parkinson's disease (PD) are the most prevalent NDs. Both diseases are poly genetic, multifactorial and heterogenous. Preventive medicine, a healthy diet, exercise, and controlling comorbidities may delay the onset. After the diseases are diagnosed, therapy is needed to slow progression. Recent studies show that local, peripheral and age-related inflammation accelerates NDs' onset and progression. Patients with autoimmune disorders like inflammatory bowel disease (IBD) could be at higher risk of developing AD or PD. However, no increase in ND incidence has been reported if the patients are adequately diagnosed and treated. Autoantibodies against abnormal tau, β amyloid and α- synuclein have been encountered in AD and PD and may be protective. This discovery led to the proposal of immune-based therapies for AD and PD involving monoclonal antibodies, immunization/ vaccines, pro-inflammatory cytokine inhibition and anti-inflammatory cytokine addition. All the different approaches have been analysed here. Future perspectives on new therapeutic strategies for both disorders are concisely examined.

Neurodegenerative disease (ND) is the fourth leading cause of death worldwide, with limited symptomatic therapies. Mitochondrial dysfunction is a major risk factor in the progression of ND, and it-increases the generation of reactive oxygen species (ROS). Overexposure to these ROS induces apoptotic changes leading to neuronal cell death. Many studies have shown the prominent effect of phytobioactive compounds in managing mitochondrial dysfunctions associated with ND, mainly due to their antioxidant properties. The drug delivery to the brain is limited due to the presence of the blood-brain barrier (BBB), but effective drug concentration needs to reach the brain for the therapeutic action. Therefore, developing safe and effective strategies to enhance drug entry in the brain is required to establish ND's treatment. The microneedle-based drug delivery system is one of the effective non-invasive techniques for drug delivery through the transdermal route. Microneedles are micronsized drug delivery needles that are self-administrable. It can penetrate through the stratum corneum skin layer without hitting pain receptors, allowing the phytobioactive compounds to be released directly into systemic circulation in a controlled manner. With all of the principles mentioned above, this review discusses microneedles as a versatile drug delivery carrier for the phytoactive compounds as a therapeutic potentiating agent for targeting mitochondrial dysfunction for the management of ND.

Background: Patients with psychotic disorders (PD) often have comorbid alcohol use disorder (AUD), which is typically treated pharmacologically. Up till now, no systematic review has examined the effectiveness and safety of AUD treatment in PD patients. Objectives: This study aimed to systematically review the literature on (1) the effects of pharmacological treatments for AUD on drinking outcomes, (2) the side effects of the drugs, and (3) the effects of polypharmacy in patients with comorbid AUD and PD. Methods: Bibliographic searches were conducted in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and PsycINFO. At least two reviewers extracted the data, assessed the risk of bias, and performed the qualitative synthesis of the collected evidence. Results: Twelve eligible studies were identified, half being randomized controlled trials (RCTs). Three studies examined disulfiram, nine naltrexone, two acamprosate, and one nalmefene by comparing the effects of treatment to placebo, baseline, or pharmacological agents. Disulfiram and naltrexone were shown to reduce alcohol intake. Regarding acamprosate, the findings were mixed. Nalmefene decreased alcohol intake. All pharmacological agents appeared safe to use as AUD monotherapy, but cardiac events were reported when combining naltrexone and disulfiram. Nine studies had a high risk of bias, and three had some other concerns. Conclusion: The studies provide tentative support for the use of naltrexone and disulfiram in this population, although combinations of pharmacological AUD treatments and other polypharmacy remain unexplored. The studies had high adherence rates that are hardly replicable in real-world settings. Thus, the findings should be confirmed in larger high quality efficacy and effectiveness RCTs with longer follow-ups.

Background: Brain recovery phenomenon after long-term abstinence had been reported in substance use disorders. Yet, few longitudinal studies have been conducted to observe the abnormal dynamic functional connectivity (dFNC) of large-scale brain networks and recovery after prolonged abstinence in heroin users.

Objective: The current study will explore the brain network dynamic connection reconfigurations after prolonged abstinence in heroin users (HUs).

Methods: The 10-month longitudinal design was carried out for 40 HUs. The 40 healthy controls (HCs) were also enrolled. Group independent component analysis (GICA) and dFNC analysis were employed to detect the different dFNC patterns of addiction-related ICNs between HUs and HCs. The temporal properties and the graph-theoretical properties were calculated. Whether the abnormalities would be reconfigured in HUs after prolonged abstinence was then investigated.

Results: Based on eight functional networks extracted from GICA, four states were identified by the dFNC analysis. Lower mean dwell time and fraction rate in state4 were found for HUs, which were increased toward HCs after prolonged abstinence. In this state, HUs at baseline showed higher dFNC of RECN-aSN, aSN- aSN and dDMN-pSN, which decreased after protracted abstinence. A similar recovery phenomenon was found for the global efficiency and path length in abstinence HUs. Mean while, the abnormal dFNC strength was correlated with craving both at baseline and after abstinence.

Conclusion: Our longitudinal study observed the large-scale brain network reconfiguration from the dynamic perspective in HUs after prolonged abstinence and improved the understanding of the neurobiology of prolonged abstinence in HUs.