Pharmacological effects of XAT on cognitive related disorders

Cognition encompasses the complex processes involved in acquiring knowledge, understanding, and responding to the world around us through thought, experience, and sensory perception [15,16,17,18]. It is the essential ability to perceive, respond, analyze, interpret, retain, retrieve data, make choices, and generate suitable responses. Rooted in the brain’s physical structure, cognition relies on more than 100 billion neurons, each capable of forming up to 10,000 connections with other neurons. These connections form intricate neural circuits that govern our thoughts and behaviors, regulated by various neurotransmitter systems, including dopamine, noradrenaline (norepinephrine), serotonin, acetylcholine, glutamate, and GABA.

Cognitive disorders represent a subset of neurocognitive disorders that significantly impede an individual’s cognitive abilities, impairing their ability to function normally in society without intervention [19,20,21,22]. These impairments can arise from congenital conditions or be acquired later in life due to various environmental factors, including brain trauma, psychiatric diseases, or neurological ailments. Numerous factors, such as chromosome abnormalities, prenatal drug exposure, trauma, and neurological disorders, can contribute to cognitive deficits across different stages of life. The emergence of our cognitive abilities arises from specific processes occurring in distinct regions of the brain, although only a subset of these activities enters our conscious awareness. While certain brain regions, like the inferior frontal gyrus, are known to play roles in specific cognitive functions such as response inhibition, mapping all aspects of cognition to finite areas of the brain remains challenging due to the diversity of human characteristics and the intricate physiology of the cortex.

The manifestation of cognitive impairments may vary widely, from mild cognitive impairment to significant neurocognitive disorders like dementia. These conditions can coexist with symptoms of other disorders, such as traumatic brain injury or neurodegenerative diseases, leading to behavioral and personality changes, unconsciousness, visual disturbances, and motor impairments. Neuronal tissue destruction underlies cognitive decline in many diseases, resulting from damage to both gray and white matter in the brain. Damage to specific regions can lead to distinct impairments in functions such as motor skills, visuospatial abilities, language, and memory. Various factors, including metabolic problems, toxins, infections, ischemia, and neurodegenerative processes, contribute to neuronal damage and cognitive decline.

The management of cognitive deficits depends on the underlying cause, with medication and therapy being the primary treatment modalities [23, 24]. However, for some conditions like amnesia, treatment may only alleviate symptoms without providing a cure. XAT, a naturally occurring compound with neuroprotective and antioxidant properties, has shown promise in treating multiple cognitive deficits. Coumarins, to which XAT belongs, possess various bioactive properties, including neuroprotective and anti-amyloid beta aggregation activities, making them potential candidates for therapeutic interventions in cognitive disorders. These compounds have contributed to advancements in therapies for prevalent cognitive illnesses, such as AD, PD, epilepsy, and depression (Fig. 7).

Fig. 7

Therapeutic activities of xanthotoxin in the treatment of cognitive-related disorders

Hence, recognizing the complex mechanisms of cognition and the fundamental causes of cognitive diseases is essential for designing efficacious treatments and interventions to enhance cognitive function and quality of life for persons suffering from such conditions.

Neuroprotective properties

Neuroprotection refers to the strategies and methodologies employed to shield the central nervous system (CNS) from harm caused by both acute incidents, such as trauma or stroke, and chronic neurodegenerative conditions, including Dementia, PD, AD, and Huntington’s disease (HD) [25, 26]. While the exact causes of nervous system disorders remain incompletely understood, extensive research using various models that simulate essential disease characteristics has identified significant factors contributing to neurological damage. These factors include oxidative stress, necrosis, cytotoxicity, ion imbalance, mitochondrial dysfunction, cellular inflammation, apoptosis, increased blood–brain permeability, and morphological changes, all of which exacerbate medical conditions and serve as indicators for identifying alternative neuroprotection strategies. Herbal medicine and nutraceuticals have emerged as valuable resources for preventing neurological problems, rather than simply treating them [27]. Extensive research has highlighted the potential of plant extracts, their bioactive components, and nutraceuticals as effective neuroprotective agents against a range of neurodegenerative conditions. The modulatory effects of phytoconstituents on the nervous system have been observed in different animal models of neurological diseases [28]. Neurotoxicity models play an important part in the designing and development of new therapeutic approaches and in evaluating the efficacy and potential adverse effects of existing symptomatic therapies [29]. Natural products and nutraceuticals exert their neuroprotective effects through distinct mechanisms. XAT, for instance, has shown promising outcomes in neurodegenerative disorders, including neurotoxicity and cognitive impairment induced by hypoxia–ischemia, AD, and PD [30, 31]. The outcomes highlight the capacity of XAT and comparable substances to reduce neuronal harm and maintain cognitive abilities in persons with neurological illnesses.

Improvement in vascular cognitive impairment in dementia

Cerebrovascular disease is the second most prevalent cause and maybe the main cause in East Asia after dementia [32]. Notably, alterations in both major and minor blood vessels within the brain, particularly those affecting small vessels in the subcortical white matter, significantly contribute to cognitive impairment associated with various conditions, including AD [33,34,35,36,37]. An expert panel has undertaken a comprehensive evaluation of vascular cognitive impairment (VCI) and vascular dementia (VaD), examining their occurrence, biological mechanisms, brain pathology, and brain imaging techniques, as well as current diagnostic and treatment methods. Mounting evidence points to several factors contributing to the development of VCI, including blood pressure variability, cardiac arrhythmia, hyperactivation of the renin–angiotensin–aldosterone system, endothelial dysfunction, vascular remodeling and stiffness, various angiopathies, neural tissue homeostasis, and systemic metabolic disorders [38].

In this context, the action of XAT has been investigated in rat thoracic aortas isolated via aortic rings, as well as in human umbilical vein endothelial cells (HUVECs) [39]. Results indicate that XAT promotes vasorelaxation by activating the KV channel and blocking the L-type Ca2 + channel, thereby stimulating the Akt-eNOS-cGMP pathway. Furthermore, XAT exhibits a suppressive effect on vascular inflammation, potentially contributing to its reported benefits in protecting blood vessels. The results of this study indicate that XAT shows potential as a form of therapy for vascular cognitive impairment, presenting a new approach to addressing cognitive problems linked to cerebrovascular illness.

Anti-inflammatory activity

Inflammation, a natural response of the body’s healing mechanism, plays a crucial role in neuronal health as well. Neuronal inflammation, also known as neuroinflammation, is a complex process involving immune cells and molecules within the CNS [40,41,42,43,44,45]. Neuroinflammation can occur as a result of several obstacles, including infection, damage, or neurodegenerative disorders. Short-term inflammation, known as acute inflammation, is the type with which we are most familiar. It occurs when we sustain an injury such as a cut, leading to swelling, redness, and pain in the affected area, typically resolving within a few hours. However, if inflammation persists and becomes chronic, it can exacerbate tissue damage and contribute to the development of various illnesses. Chronic inflammation, lasting for extended periods ranging from months to years, is a significant factor in over 50% of global mortality. The development of various neurological illnesses, such as AD, PD, multiple sclerosis (MS), and stroke, has been associated with chronic neuroinflammation. Encephalitis refers to inflammation of the brain, while myelitis refers to inflammation of the spinal cord. In addition, encephalomyelitis is another condition affecting both the brain and spinal cord. Infections and other illnesses affecting the brain and spinal cord can trigger inflammation as part of the immune response. In these conditions, inflammatory responses within the brain can lead to neuronal damage and cognitive impairment.

Previous research has shown evidence that XAT demonstrates anti-inflammatory properties by reducing the release of pro-inflammatory cytokines and suppressing the activation of inflammatory pathways. These effects have the potential to be advantageous in the context of brain inflammation [46]. Several studies have been undertaken to assess the anti-inflammatory properties of 8-MOP on different cell types, such as bovine mammary epithelial cells (BMECs) and the macrophage cell line RAW264.7. These cell lines were stimulated with lipopolysaccharide (LPS), which is known to induce inflammation [47]. Results demonstrated that 8-MOP exhibited significant anti-inflammatory effects, particularly at a concentration of 25 μg/mL. Western blot analysis revealed that 8-MOP inhibited the activation of NF-κB and JNK/STAT pathways, key players in inflammatory signaling. Furthermore, it has been demonstrated through in vivo experiments that 8-MOP effectively inhibits the secretion of pro-inflammatory molecules, including IL-1β, IL-6, IL-8, and TNF-κ, from immune cells such as neutrophils, macrophages, and lymphocytes. This mechanism of action serves to safeguard cells against inflammatory harm [48]. The results of this study indicate that XAT may have therapeutic promise in the treatment of disorders related to inflammation.

Antioxidant activity

Oxidative stress occurs when there is an imbalance between the generation and buildup of reactive oxygen species (ROS) in cells and tissues, and the ability of the biological system to remove these reactive substances [49,50,51,52]. The generation of ROS is crucial for various physiological processes, including cell signaling. However, excessive ROS production resulting from environmental stressors such as ultraviolet (UV) radiation, ionizing radiation, pollution, heavy metals, and xenobiotics such as anticlastic medications can induce oxidative stress, which can result in cellular and tissue damage. Oxidative stress in the brain is a major factor in the onset and advancement of various neurological illnesses, including depression, Parkinson’s disease, and cognitive impairments in AD. The experience of stress results in detrimental effects on proteins, lipids, and other cellular constituents, as indicated by several indicators including heightened concentrations of protein carbonyls, 3-nitrotyrosine, protein-bound 4-hydroxynonenal, and raised levels of isoprostanes or neuroprostanes [53].

In recent years, antioxidants like vitamin E, flavonoids, and polyphenols have been studied for their ability to counteract oxidative stress. XAT functions as an antioxidant primarily by removing harmful free radicals and binding metal ions that promote oxidation. Additionally, XAT suppresses enzyme activity to regulate reactive oxygen species levels within the normal range. Research has indicated that XAT exhibits therapeutic promise across a range of illnesses. It induces the phosphorylation of AMPKΑ and inhibits the phosphorylation of NF-κB in animals with osteoarthritis via the SITR1/NF-κB pathway, resulting in pain alleviation and decreased oxidative stress response [54]. Furthermore, XAT has been found to suppress apoptosis mediated by IL-1β in chondrocytes, hence mitigating the presence of inflammatory stimuli. Additionally, this substance may possess therapeutic attributes for diabetes through its ability to inhibit aldose reductase (AR), thereby regulating the amounts of reactive oxygen species in a state of equilibrium [55, 56]. XAT exerts its antioxidant properties through the activation of nuclear factor E2-related factor-2 (Nrf2). The regulation of cellular response to oxidative stress is governed by Nrf2, which triggers the activation of antioxidant genes such as heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) [57]. The results of this study indicate that XAT exhibits potential as a pharmacological drug possessing antioxidant characteristics, hence presenting possible therapeutic advantages in a range of disorders associated with oxidative stress.

Antiepileptic activity

Epilepsy, affecting approximately 50 million people globally, is identified by recurrent seizures, ranging from short muscle jerks to severe convulsions, caused by excessive electrical discharges in the brain. Alarmingly, 80% of epilepsy cases occur in low- and middle-income countries, where access to treatment is limited. While effective diagnosis and treatment could lead to seizure-free lives for 70% of individuals, many face stigma and discrimination [58, 59]. Seizures often accompany temporary symptoms like loss of consciousness and physical injuries, while psychological conditions such as anxiety and depression are common [60,61,62,63,64]. Despite its multifaceted causes, epilepsy can be managed with antiseizure medications, offering hope for improved quality of life with proper support. Regarding the effect of XAT on epilepsy, several studies have demonstrated its potential as an antiepileptic agent.

The study was conducted by Adak et al. to explore the possibility of XAT in augmenting the anticonvulsant efficacy of Rauwolfia serpentina in experimental animals with chemically induced convulsions [65]. Utilizing Pentylenetetrazol (PTZ) and Strychnine HCL models, they compared the effects of XAT with the standard dose of Diazepam. The study aimed to assess the concentrations of GABA in the brain to gain a deeper understanding of the underlying mechanisms responsible for the anticonvulsant effect. The findings of the study indicated that the administration of XAT intraperitoneally at doses of 50 and 100 mg/kg had a considerable enhancement of the anticonvulsant properties of Rauwolfia serpentina. Furthermore, the administration of XAT at a dosage of 100 mg/kg intraperitoneally emphasized the anticonvulsant properties of Rauwolfia serpentina. Additionally, it exhibited a significant and dose-dependent inhibition of convulsions generated by PTZ and Strychnine. Additionally, co-administration of XAT and Rauwolfia serpentina led to a notable elevation of GABA levels in the brain, exceeding those observed with Rauwolfia serpentina alone. Notable parameters measured included seizure latency, duration, and mortality, all of which indicated a significant anticonvulsant effect with the combined administration of XAT and Rauwolfia serpentina.

Zagaja et al. [66] conducted a study to examine the effects of XAT on the anticonvulsant capabilities of four traditional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, and valproate) using the mouse maximal electroshock seizure paradigm. The findings of the study revealed that the administration of XAT intraperitoneally at a dosage of 100 mg/kg markedly improved the efficacy of valproate in the prevention of seizures during the maximal electroshock seizure test conducted by researchers [66]. In contrast, the administration of XAT did not demonstrate any significant impact on the efficacy of phenobarbital and phenytoin in mitigating seizures generated by maximal electroshock in mice. In addition, the intraperitoneal delivery of XAT at a dosage of 100 mg/kg led to a notable elevation in the total concentrations of carbamazepine and valproate inside the brain. Conversely, there was no notable change in the concentrations of phenytoin and phenobarbital, suggesting that interactions between these medications are primarily influenced by their pharmacokinetics. In general, the reported synergistic effects in mice resulting from the combination of XAT with carbamazepine and valproate are likely attributable to an elevation in the intracranial levels of these antiepileptic drugs in experimental subjects, principally attributable to alterations in their pharmacokinetics.

In their study, Zagaja et al. examined the influence of XAT on the preventive properties of five distinct second- and third-generation antiepileptic drugs (lacosamide, lamotrigine, oxcarbazepine, pregabalin, and topiramate) in a murine model of seizures caused by maximal electroshock [67]. The researchers observed that the intraperitoneal administration of XAT at a dosage of 100 mg/kg resulted in a considerable increase in the efficacy of lacosamide, oxcarbazepine, pregabalin, and topiramate as anticonvulsant medications. Nevertheless, the impact of the respective substances on lamotrigine in the maximal electroshock-induced seizure test was not seen. In the seizure test, the administration of XAT at a dosage of 50 mg/kg resulted in a significant enhancement of the anticonvulsant effects of lacosamide (P < 0.05), pregabalin (P < 0.05), and topiramate (P < 0.001). The administration of XAT did not have a significant impact on the total levels of the antiepileptic medications that were tested in the mouse brain. No adverse effects were seen when XAT was administered concurrently with oxcarbazepine or topiramate. In the grip-strength test, it was shown that the co-administration of XAT with lacosamide, lamotrigine, or pregabalin led to a significant reduction in muscle strength in mice. The chimney test revealed a notable adverse impact on motor coordination in mice just when XAT was combined with pregabalin. In the maximal electroshock-induced seizure test, the concurrent administration of XAT with oxcarbazepine and topiramate demonstrates favorable pharmacodynamic interactions against convulsants. The combination of XAT and pregabalin should be approached with caution due to the potential occurrence of acute adverse effects.

The anticonvulsant effects of XAT, derived from the fruit of Pastinaca sativa L., a herb frequently employed in traditional European medicine, namely in Poland, were examined by Skalicka-Woźniak et al. [68]. The efficacy of XAT in preventing seizures was evaluated in mice by the maximal electroshock-induced seizure test, which demonstrated a clear and significant anticonvulsant effect. The median effective doses (ED50 values) obtained through experimental methods varied between 219 and 252 mg/kg [68].

In a study conducted by Łuszczki et al., the anticonvulsant effects of four natural furanocoumarins, namely bergapten (5-methoxypsoralen), imperatorin (8-isopentenyloxypsoralen), oxypeucedanin (5-epoxy-isopentenyloxypsoralen), and XAT, were compared. The study employed the maximal electroshock-induced seizure test in mice [69]. The research findings demonstrated notable anticonvulsant efficacy of imperatorin and XAT, which are both derivatives of psoralen with C-8 substitutions when administered at a dosage of 300 mg/kg. Nevertheless, bergapten and oxypeucedanin, which are derivatives of psoralen with C-5 substitutions, did not exhibit any anticonvulsant efficacy when administered at the same dosage. In this seizure test, it was observed that imperatorin and XAT displayed protective effects against seizures induced by maximal electroshock. However, bergapten and oxypeucedanin did not exhibit any anticonvulsant activity.

Furthermore, XAT showed substantial effectiveness in preventing epileptic seizures in the 6-Hz corneal stimulation-induced convulsions model. XAT demonstrated independent antiepileptic activity, and its antiepileptic effects were further augmented when provided in conjunction with the frequently employed antiepileptic medications levetiracetam and valproate. The administration of levetiracetam in combination with XAT resulted in a drop in the ED50 from 19.37 to 2.83 mg/kg, whereas the ED50 of valproate reduced from 92.89 to 44.44 mg/kg [70]. In brief, XAT modifies the CNS to alleviate excessive pathogenic activity, hence presenting a potential supplementary approach to antiepileptic pharmaceuticals for the management of epilepsy. This approach involves decreasing the necessary dosage of antiepileptic drugs.

Antidepressant activity

Depression is a prevalent medical illness that is distinguished by enduring emotions of sorrow, diminished engagement in activities, and impaired everyday functioning that lasts for a minimum duration of two weeks. Additional symptoms include changes in appetite, sleep patterns, anxiety, indecisiveness, and thoughts of self-harm or suicide [71,72,73]. Various factors contribute to depression, including genetics, chronic illness, social issues, and substance abuse. The global prevalence of depression exceeds 300 million, with India alone reporting 15% of adults needing mental health support and 1 in 20 individuals affected by depression. Depression is a leading cause of disability worldwide, with severe cases potentially leading to suicide, which claims around 800,000 lives annually, particularly among young adults. Despite effective treatments, less than half of those affected receive adequate care due to resource limitations, insufficient training of healthcare professionals, and social stigma [74,75,76]. Prevention programs, including school-based initiatives and government healthcare programs like the National Mental Health Programme in India, aim to address these challenges and provide support to those affected by depression. Several studies have indicated the potential of XAT as an antidepressant agent, suggesting its efficacy in managing epilepsy.

Kowalczyk et al. assessed the impact of XAT on depression-like behaviors in male and female Swiss mice and explored the underlying mechanism of this action [77]. The application of naturally occurring furanocoumarin (from the Apiaceae family), specifically XAT, at a single dose of 12.5 mg/kg, resulted in a reduction in the level of immobility observed during the forced swim test, but only in male subjects. Females exhibited reduced immobility compared to males, potentially due to an elevated serotonin level in the prefrontal brain of females. An increase in serotonin and noradrenaline was observed in the female prefrontal cortex using reverse-phase ion-pair liquid chromatography. However, no such increase was observed in the hippocampus. The increase in neurotransmitters was found to be dependent on the amount administered. It is proposed that XAT may possess antidepressant qualities and have varying effects on males and females. This impact may be attributed to the elevated serotonin levels in the prefrontal brain of both males and females. Moreover, it has been proposed that XAT may possess the ability to restrict the levels of MAO, and heightened MAO expression is considered to play a substantial part in the development of depression. In conclusion, XAT is an effective treatment for pathological depression and has the potential to enhance mood by increasing the generation of 5-HT and NA, mostly by inhibiting MAO activity [78].

Anti-Alzheimer’s activity

AD is the prevailing form of dementia, accounting for approximately 60–70% of cases. It presents itself gradually, commencing with mild memory impairment and advancing toward substantial cognitive deterioration. This condition affects brain regions responsible for cognition, memory, and language, impairing daily functioning [79,80,81,82]. Although onset can occur in younger individuals, it primarily affects older adults, with prevalence doubling every five years after age 65. While exact causes remain unclear, factors such as advanced age, lifestyle choices, genetics, cardiovascular disease, autoimmune conditions, traumatic brain injury, and mild cognitive impairment increase susceptibility. However, research suggests that adopting healthy lifestyle habits like regular physical activity and managing blood pressure may reduce dementia risk. Although treatment is not yet available, medical therapies are designed to enhance the overall well-being of patients and their caregivers. XAT’s therapeutic potential offers hope for AD treatment. Recent studies have shown therapeutic potential for XAT in treating AD, a form of dementia characterized by cognitive decline.

Hindam et al. evaluated the neuroprotective properties of XAT and umbelliferone in rats with cognitive impairment produced by streptozotocin (STZ) [83]. To induce a condition resembling sporadic Alzheimer’s disease (SAD), a single intracerebroventricular injection of STZ (3 mg/kg) was administered to the animals. XAT and umbelliferone, at a dosage of 15 mg/kg, were injected intraperitoneally (i.p.) 5 h after intracerebroventricular injection of streptozotocin (ICV-STZ) and continued daily for 20 consecutive days. XAT and umbelliferone exhibited neuroprotective effects, mitigating cognitive impairments observed in the Morris water maze and object recognition tests. Simultaneously, XAT and umbelliferone decreased the activity of acetylcholinesterase and the quantity of malondialdehyde in the hippocampus. Furthermore, the presence of XAT or umbelliferone resulted in an elevation of glutathione levels. The coumarins exhibited regulatory effects on neuronal cell death through the reduction of pro-inflammatory cytokine levels (specifically tumor necrosis factor-alpha and interleukin-6), inhibition of excessive inflammatory marker production (specifically nuclear factor κB [NF-κB] and cyclooxygenase-II), and increase in NF-κB inhibitor (IκB-α) expression. The administration of XAT resulted in a decrease in the quantities of phosphorylated JAK2 and phosphorylated STAT3 proteins, while umbelliferone exhibited a notable increase in the levels of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). The study presented empirical evidence supporting the preventative efficacy of XAT and umbelliferone in rats exhibiting cognitive impairment produced by STZ. The observed effect can be partially attributed to the suppression of acetylcholinesterase and the mitigation of oxidative stress, neuroinflammation, and neuronal demise.

While coumarins have shown promise in enhancing cognitive function and possessing anti-inflammatory properties, their precise mechanism of neuroprotection remains unclear. Karachi et al. conducted a study to examine the neuroprotective properties of XAT and umbelliferone in mice with cognitive impairment produced by lipopolysaccharide [