Current Neuropharmacology - Volume 21, Issue 4, 2023

Alzheimer's is a chronic neurodegenerative disease where amyloid-beta (Aβ) plaques and neurofibrillary tangles are formed inside the brain. It is also characterized by progressive memory loss, depression, neuroinflammation, and derangement of other neurotransmitters. Due to its complex etiopathology, current drugs have failed to completely cure the disease. Natural compounds have been investigated as an alternative therapy for their ability to treat Alzheimer's disease (AD). Traditional herbs and formulations which are used in the Indian ayurvedic system are rich sources of antioxidant, anti-amyloidogenic, neuroprotective, and anti-inflammatory compounds. They promote quality of life by improving cognitive memory and rejuvenating brain functioning through neurogenesis. A rich knowledge base of traditional herbal plants (Turmeric, Gingko, Ashwagandha, Shankhpushpi, Giloy, Gotu kola, Garlic, Tulsi, Ginger, and Cinnamon) combined with modern science could suggest new functional leads for Alzheimer's drug discovery. In this article Ayurveda, the ancient Indian herbal medicine system based on multiple clinical and experimental, evidence have been reviewed for treating AD and improving brain functioning. This article presents a modern perspective on the herbs available in the ancient Indian medicine system as well as their possible mechanisms of action for AD treatment. The main objective of this research is to provide a systematic review of herbal drugs that are easily accessible and effective for the treatment of AD.

Phytochemicals or natural products have been studied extensively for their potential in the treatment of neurodegenerative diseases (NDs) like Parkinson’s disease, Alzheimer’s disease, etc. The neuronal structure loss and progressive dysfunction are the main characteristics of these diseases. In spite of impressive and thorough knowledge of neurodegenerative molecular pathways, little advancement has been found in the treatment of the same. Moreover, it was proved that natural products can be used efficiently in the treatment of NDs while certain issues regarding the patient's safety and clinical data are still existing. As ND is a bunch of diseases and it will start the myriad of pathological processes, active targeting of the molecular pathway behind ND will be the most efficient strategy to treat all ND-related diseases. The targeting pathway must prevent cell death and should restore the damaged neurons. In the treatment of ND and related diseases, natural products are playing the role of neuroprotective agents. This review will target the therapeutic potential of various phytochemicals which shows neuroprotective action.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that mostly affects the elderly population. Mechanisms underlying AD pathogenesis are yet to be fully revealed, but there are several hypotheses regarding AD. Even though free radicals and inflammation are likely to be linked with AD pathogenesis, still amyloid-beta (Aβ) cascade is the dominant hypothesis. According to the Aβ hypothesis, a progressive buildup of extracellular and intracellular Aβ aggregates has a significant contribution to the AD-linked neurodegeneration process. Since Aβ plays an important role in the etiology of AD, therefore Aβ-linked pathways are mainly targeted in order to develop potential AD therapies. Accumulation of Aβ plaques in the brains of AD individuals is an important hallmark of AD. These plaques are mainly composed of Aβ (a peptide of 39-42 amino acids) aggregates produced via the proteolytic cleavage of the amyloid precursor protein. Numerous studies have demonstrated that various polyphenols (PPHs), including cyanidins, anthocyanins, curcumin, catechins and their gallate esters were found to markedly suppress Aβ aggregation and prevent the formation of Aβ oligomers and toxicity, which is further suggesting that these PPHs might be regarded as effective therapeutic agents for the AD treatment. This review summarizes the roles of Aβ in AD pathogenesis, the Aβ aggregation pathway, types of PPHs, and distribution of PPHs in dietary sources. Furthermore, we have predominantly focused on the potential of food-derived PPHs as putative anti-amyloid drugs.

Neurodegeneration is the progressive loss of structure or function of neurons, which may ultimately involve cell death. The most common neurodegenerative disorder in the brain happens with Alzheimer's disease (AD), the most common cause of dementia. It ultimately leads to neuronal death, thereby impairing the normal functionality of the central or peripheral nervous system. The onset and prevalence of AD involve heterogeneous etiology, either in terms of genetic predisposition, neurometabolomic malfunctioning, or lifestyle. The worldwide relevancies are estimated to be over 45 million people. The rapid increase in AD has led to a concomitant increase in the research work directed towards discovering a lucrative cure for AD. The neuropathology of AD comprises the deficiency in the availability of neurotransmitters and important neurotrophic factors in the brain, extracellular betaamyloid plaque depositions, and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Current pharmaceutical interventions utilizing synthetic drugs have manifested resistance and toxicity problems. This has led to the quest for new pharmacotherapeutic candidates naturally prevalent in phytochemicals. This review aims to provide an elaborative description of promising Phyto component entities having activities against various potential AD targets. Therefore, naturopathy may combine with synthetic chemotherapeutics to longer the survival of the patients.

Alzheimer's and Parkinson's are neurodegenerative disorders that affect a great number of people around the world, seriously compromising the quality of life of individuals, due to motor and cognitive damage. In these diseases, pharmacological treatment is used only to alleviate symptoms. This emphasizes the need to discover alternative molecules for use in prevention. Using Molecular Docking, this review aimed to evaluate the anti-Alzheimer’s and anti-Parkinson’s activity of linalool and citronellal, as well as their derivatives. Before performing Molecular Docking simulations, the compounds’ pharmacokinetic characteristics were evaluated. For Molecular Docking, 7 chemical compounds derived from citronellal, and 10 compounds derived from linalool, and molecular targets involved in Alzheimer's and Parkinson's pathophysiology were selected. According to the Lipinski rules, the compounds under study presented good oral absorption and bioavailability. For toxicity, some tissue irritability was observed. For Parkinson-related targets, the citronellal and linalool derived compounds revealed excellent energetic affinity for α-Synuclein, Adenosine Receptors, Monoamine Oxidase (MAO), and Dopamine D1receptor proteins. For Alzheimer disease targets, only linalool and its derivatives presented promise against BACE enzyme activity. The compounds studied presented high probability of modulatory activity against the disease targets under study, and are potential candidates for future drugs.

Huntington’s disease (HD) is a rare and fatal neurodegenerative disorder with no diseasemodifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. In fact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibitors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various other diseases in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease- modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In this review, we have discussed HD pathogenesis and summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanism/s.

Lithium is most well-known for its mood-stabilizing effects in the treatment of bipolar disorder. Due to its narrow therapeutic window (0.5-1.2 mM serum concentration), there is a stigma associated with lithium treatment and the adverse effects that can occur at therapeutic doses. However, several studies have indicated that doses of lithium under the predetermined therapeutic dose used in bipolar disorder treatment may have beneficial effects not only in the brain but across the body. Currently, literature shows that low-dose lithium (≤0.5 mM) may be beneficial for cardiovascular, musculoskeletal, metabolic, and cognitive function, as well as inflammatory and antioxidant processes of the aging body. There is also some evidence of low-dose lithium exerting a similar and sometimes synergistic effect on these systems. This review summarizes these findings with a focus on low-dose lithium’s potential benefits on the aging process and age-related diseases of these systems, such as cardiovascular disease, osteoporosis, sarcopenia, obesity and type 2 diabetes, Alzheimer’s disease, and the chronic low-grade inflammatory state known as inflammaging. Although lithium’s actions have been widely studied in the brain, the study of the potential benefits of lithium, particularly at a low dose, is still relatively novel. Therefore, this review aims to provide possible mechanistic insights for future research in this field.

Background: Bipolar Disorder (BD) is a highly comorbid condition, and rates of cooccurring disorders are even higher in youth. Comorbid disorders strongly affect clinical presentation, natural course, prognosis, and treatment. Methods: This review focuses on the clinical and treatment implications of the comorbidity between BD and Attention-Deficit/Hyperactivity Disorder, disruptive behavior disorders (Oppositional Defiant Disorder and/or Conduct Disorder), alcohol and substance use disorders, Autism Spectrum Disorder, anxiety disorders, Obsessive-Compulsive Disorder, and eating disorders. Results: These associations define specific conditions which are not simply a sum of different clinical pictures, but occur as distinct and complex combinations with specific developmental pathways over time and selective therapeutic requirements. Pharmacological treatments can improve these clinical pictures by addressing the comorbid conditions, though the same treatments may also worsen BD by inducing manic or depressive switches. Conclusion: The timely identification of BD comorbidities may have relevant clinical implications in terms of symptomatology, course, treatment and outcome. Specific studies addressing the pharmacological management of BD and comorbidities are still scarce, and information is particularly lacking in children and adolescents; for this reason, the present review also included studies conducted on adult samples. Developmentally-sensitive controlled clinical trials are thus warranted to improve the prognosis of these highly complex patients, requiring timely and finely personalized therapies.

Bipolar disorders (BDs) are a heterogeneous group of severe affective disorders generally described by the alternation of (hypo)manic, depressive, and mixed phases, with euthymic intervals of variable duration. BDs are burdened with high psychiatric and physical comorbidity, increased suicide risk and reduced life expectancy. In addition, BDs can progress into complicated forms (e.g., mixed states, rapid/irregular cycling), which are more difficult to treat and often require personalized pharmacological combinations. Mood stabilizers, particularly Lithium and Valproic acid (VPA), still represent the cornerstones of both acute and chronic pharmacotherapies of BDs. Lithium is the gold standard in BD-I and BDII with typical features, while VPA seems more effective for atypical forms (e.g., mixed-prevalence and rapid-cycling). However, despite appropriate mood stabilization, many patients show residual symptoms, and more than a half recur within 1-2 years, highlighting the need of additional strategies. Among these, the association of atypical antipsychotics (AAPs) with mood stabilizers is recurrent in the treatment of acute phases, but it is also being growingly explored in the maintenance pharmacotherapy. These combinations are clinically more aggressive and often needed in the acute phases, whereas simplifying pharmacotherapies to mood stabilizers only is preferable in the long-term, whenever possible. When mood stabilizers are not enough for maintenance treatment, Quetiapine and, less consistently, Aripiprazole have been proposed as the most advisable adjunctive strategies, for their safety and tolerability profiles. However, in view of the increased risk of serious adverse effects, a careful patient-centered balance between costs and benefits is mandatory.

The use of exogenous melatonin (exo-MEL) as a sleep-promoting drug has been under extensive debate due to the lack of consistency of its described effects. In this study, we conduct a systematic and comprehensive review of the literature on the chronobiotic, sleep-inducing, and overall sleep-promoting properties of exo-MEL. To this aim, we first describe the possible pharmacological mechanisms involved in the sleep-promoting properties and then report the corresponding effects of exo-MEL administration on clinical outcomes in: a) healthy subjects, b) circadian rhythm sleep disorders, c) primary insomnia. Timing of administration and doses of exo-MEL received particular attention in this work. The exo-MEL pharmacological effects are hereby interpreted in view of changes in the physiological properties and rhythmicity of endogenous melatonin. Finally, we discuss some translational implications for the personalized use of exo-MEL in the clinical practice.

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders, affecting the basal nuclei, causing impairment of motor and cognitive functions. Loss of dopaminergic (DAergic) neurons or their degeneration and the aggregation of Lewy bodies is the hallmark of this disease. The medications used to treat PD relieve the symptoms and maintain quality of life, but currently, there is no cure. There is a need for the development of therapies that can cease or perhaps reverse neurodegeneration effectively. With the rapid advancements in cell replacement therapy techniques, medical professionals are trying to find a cure by which restoration of dopamine neurotransmitters can occur. Researchers have started focusing on cell-based therapies using mesenchymal stem cells (MSCs) due to their abundance in the body, the ability of proliferation, and immunomodulation. Here we review the MSC-based treatment in Parkinson's disease and the various mechanisms it repairs DAergic neurons in parkinsonian patients.

Traumatic brain injury (TBI) is one of the significant causes of death and morbidity, and it is hence a focus of translational research. Apoptosis plays an essential part in the pathophysiology of TBI, and its inhibition may help overcome TBI's negative consequences and improve functional recovery. Although physiological neuronal death is necessary for appropriate embryologic development and adult cell turnover, it can also drive neurodegeneration. Caspases are principal mediators of cell death due to apoptosis and are critical for the required cleavage of intracellular proteins of cells committed to die. Caspase-3 is the major executioner Caspase of apoptosis and is regulated by a range of cellular components during physiological and pathological conditions. Activation of Caspase-3 causes proteolyzation of DNA repair proteins, cytoskeletal proteins, and the inhibitor of Caspase-activated DNase (ICAD) during programmed cell death, resulting in morphological alterations and DNA damage that define apoptosis. Caspase-9 is an additional crucial part of the intrinsic pathway, activated in response to several stimuli. Caspases can be altered post-translationally or by modulatory elements interacting with the zymogenic or active form of a Caspase, preventing their activation. The necessity of Caspase-9 and -3 in diverse apoptotic situations suggests that mammalian cells have at least four distinct apoptotic pathways. Continued investigation of these processes is anticipated to disclose new Caspase regulatory mechanisms with consequences far beyond apoptotic cell death control. The present review discusses various Caspase-dependent apoptotic pathways and the treatment strategies to inhibit the Caspases potentially.

Objective: Evidence has shown that brain-derived neurotrophic factor (BDNF) is associated with anhedonia symptoms in major depressive disorder (MDD) patients, while the rapid antianhedonic effects of ketamine may occur independently of depressive symptoms. To our knowledge, the relationship between plasma BDNF (pBDNF) and the effect of repeated-dose intravenous ketamine on anhedonic symptoms has not been investigated. Methods: Seventy-five Chinese individuals with MDD received ketamine treatments. Anhedonia and pBDNF concentrations were evaluated with a subscale of the Montgomery-Åsberg Depression Rating Scale (MADRS) and enzyme-linked immunosorbent assay (ELISA) at baseline, day 13 and day 26. Results: Baseline pBDNF levels were associated with changes in anhedonic symptoms on day 13 (r=0.30, P=0.008). Interestingly, pBDNF concentrations were associated with changes in anhedonia symptomson day 26 (r= -0.32, P=0.02). Baseline pBDNF levels were higher in antianhedonic responders than in antianhedonic nonresponders (F=4.2, P=0.04). Ketaminereduced anhedonia symptoms in antianhedonic responders compared to nonresponders on days 13 and 26 (all Ps<0.05). The baseline high BDNF group had a lower level of anhedonia than the low BDNF group on days 13 (P<0.001) and 26 (P=0.01). Conclusion: Our study suggests that baseline pBDNF concentrations may predict the antianhedonic effect in individuals with MDD treated with repeated doses of ketamine.