An Updated List of Neuromedicinal Plants of Pakistan, Their Uses, and Phytochemistry

Background Almost every region of Pakistan is stacked with a large number of medicinal plants. Due to high cost and unavailability of allopathic medicines for the neurological diseases, especially in rural areas, traditional healers prescribe phytotherapy for various neurological diseases like epilepsy, depression, anxiety, insomnia, Alzheimer, and migraine. Such treatments are considered to be most effective by the native people. Methods The data was collected from articles published on medicinal plants of various districts of Pakistan, using article search engines like Medline, Pubmed, Web of Science, Science Direct, and Google Scholar. Also, information regarding various neurological uses and mode of applications of medicinal plants was obtained from traditional healers, folk medicine users, and local elderly people having knowledge of medicinal plants. Results A total of 54 families were found to be used in various neurological diseases, of which the highest use was of Solanaceae (22.22%), Asteraceae (12.96%), Lamiaceae, Papaveraceae, and Poaceae, 9% each, and Caprifoliaceae, Cucurbitaceae, Rhamnaceae, and Rosaceae, 5.5% each. According to districts, 15% of plants that were effective in neurological affections were found in Bahawalpur, 11% in Swat, 8% in Muzaffarabad, 7% in Malakand, and 6% in Bahawalnagar, Dir, Gilgat, and Sarghoda each, with 5% in Dera ghazi khan and Jhelum each. According to the plant's habit, out of total of 103 plants, 61.15% were found to be herbs, 22.33% trees, 11.65% shrubs, and 4.85% climbers. According to the part used of plant, whole plant, leaves, fruits, roots, seeds, and flowers were found to be used 32.03%, 24.27%, 20.38%, 16.50%, 13.59%, and 11.65%, respectively. According to disease's types, 45.63% were found to be effective in insomnia, 31.06% in epilepsy 12.62% in depression, 6.80% in anxiety, 7.77% in hysteria, and 5.88% in migraine. Conclusion Taking into consideration this useful knowledge on medicinal properties of the plants for curing neurologic diseases, it is believed that research in areas of ethnomedicine and ethnopharmacology can bring auspicious results that have potential of adding value to the very rich natural resources of Pakistan. This study will help all the researchers from diverse backgrounds working on plants based medicine for neurological diseases.


Introduction
Globally, neurological diseases are among the major contributors to mortality and morbidity, particularly in developing nations. The well-known manifestations of neurological diseases include mood swing, restlessness, hopelessness, poor coordination, seizures, impaired cognition, paralysis, distress of sensation, muscle weakness, pain, and confusion [1]. There are more than six hundred neurological diseases, some of which are relatively common and well known while others are rare or poorly recognized [2]. Demographic, socioeconomic, and geographic conditions are the major factors affecting epidemiology of neurological diseases. Globally, the overall burden of neurological diseases is about 6.5%. In lower income countries, neurological diseases range from 4 to 5%, as compared to high income countries where such diseases range from 10 to 11%. This high ratio of neurological diseases in advanced countries may be due to their more advanced public health system and health-related facilities that provide and maintain complete data of their patients [1].
About 45 million people of the world, above 18 years of age, suffer from schizophrenia at some stage of their lives, 340 million are affected by depression, and both these diseases are accountable for 60 % of all suicides, while Alzheimer and epilepsy affect about 11 and 45 million people, respectively, around the world accounting for 1% of the total disease burden in the world [3].
In Pakistan, about 10 % people suffer from mental diseases, representing a foggy picture with 2% prevalence of ' epilepsy, 5% depression, 1% Alzheimer, and 1.5% schizophrenia [4] as shown in (Table 1). These mental morbidities are responsible for high suicidal rate. Major factors contributing to this alarming increase in mental diseases are unemployment, poverty, political unreliability, violence, and other social horrors and evils beyond the genetic and biological susceptibility [5].
Medicinal plants have been used from the very beginning in health care systems. Studies have been carried out globally to verify their efficacy and some of the findings have led to the production of plant-based medicines. Due to limited access to modern medicine, the local population uses medicinal plants to treat most diseases [6,7]. Recent focus on plant research has increased worldwide and most evidence has been collected to determine the immense potential of medicinal plants [8]. Medical plants have therapeutic benefits and fewer side effects in comparison with synthetic drugs [9]. Drugs used for neurological diseases along with their side effects are given in (Table 2).
Herbs may provide a source of new compounds including many drugs that are derived from plant sources. For several neurological diseases, modern medicine offers symptomatic treatment that is often expensive and associated with side effects. Indian system of medicine has traditionally been used in several neurological conditions. The accessibility, cost effectiveness, and lower incidence of side effects of plant products offer considerable advantages [10].
Various plant extracts have been screened and investigated for their potential neuropharmacological activities in different experimental models of animals comprising mice and rats. Herbal extracts and natural products including Bacopa monnieri, Cannabis sativa, Solanum nigrum, Withania somnifera, Papaver somniferum, Zizyphus jujube, Tribulus terrestris, and Verbena officinalis showed different neuropharmacological activities. These agents can be used alone or as adjuncts to standard drugs, used for various neurological diseases like depression, epilepsy, schizophrenia, Alzheimer, Parkinson, hysteria, melancholia, and dementia, for increasing their efficacy and decreasing side effects.
In developing countries, plant-based medicines are being used by 75-80% of population [11]. The knowledge of indigenous medicinal plants is a part of Pakistani culture and traditionally, majority of Pakistani people use herbal medicines for various diseases [12].
In Pakistan, folk medicines have more use in rural and less developed areas for the treatment of various diseases because of easy access, cost effectiveness, less side effects, and unavailability of allopathic therapeutic agents [13]. This type of treatment, using traditional medicinal flora, is practiced regularly in homes and transferred from generation to generation as a cultural virtue. However, this tradition and associated knowledge are diminishing rapidly due to negligence and less interest of new generation to receive this gift of ethnomedicinal prosperity from their ancestors. Various parameters like industrialization, migration from rural to urban areas for education and jobs, passion towards advanced lifestyles, deforestation, and allopathic medicine might have brought this change in behavior. Therefore, before it is lost forever, this valuable traditional knowledges need to be urgently collected and systematically documented for the interest of humanity [14].   Direct, and Google Scholar, by using special key words "medicinal plants", herbal plants, neurological diseases, specific districts names, antialzheimer, antiparkinson, antidepression, sedative, anxiolytic, antiepileptics, epidemiology, and prevalence, from January to March 2018, and downloaded. These entire articles were then viewed and the data of medicinal plants, which have neurological effects, were collected and tabulated in (   Figure 1).   This district-wise plant distribution will help the researchers, who are willing to research in neuropharmacological area, to easily collect the target plants from the regions to which the plants belong. According to the plant's habit, out of total of 103 plants, 61.15% were found to be herbs, 22.33 % trees, 11.65% shrubs, and 4.85% climbers ( Figure 2).

Results and Discussion
The habit of plants shows that herbs are most important according to neuropharmacological point of view which is another benefit for researchers working in neuropharmacological area to concentrate on herbs more while selecting neurological active plants. According to the part used of plant, whole plant, leaves, fruits, roots, seeds, flowers, and other parts (bulbs, latex, gum, tubers, and rhizome) were found to be used 32. have more than one part to be used for various neurological diseases, so such plants were counted into percentage of all respective parts. This division of neuropharmacological plants ensures the researchers to select the most appropriate parts of plants having specific neuropharmacological activities, for their research, as used by traditional healers and folk medicine users. According to disease's types, 45.63 % were found to be of therapeutic value in insomnia, epilepsy (31.06%), depression (12.62%), anxiety (6.80%), hysteria (7.77%), and migraine (5.88%) and 20.38 % in other neurological diseases (neuralgia, mania, Parkinson, schizophrenia, and nerve pain) ( Figure 4). As some plants are used for multiple neurological ailments, so such plants were counted into percentage of all respective diseases. This disease-wise plant division will help the local researchers to select their interest areas in the field of neuropharmacology, by selecting the neurological disease, for which most of the plant's percentage was found to be used by traditional healers and folk medicine users in various districts of Pakistan.
These chemical constituents of plants act on the central nervous system through various mechanisms including regulation of neurotransmitters like adrenergic, cholinergic and serotonergic activity, acting through receptor like GABA and N-methyl-D-aspartate, and ion channels like sodium, potassium, and calcium ion channels. Some of the plantbased drugs and phytochemicals which either are approved or are under clinical trials for the treatment of neurological diseases, mechanism of actions, and their current status in clinical trials are given in (Table 5).
Taking into consideration this useful knowledge on the medicinal properties of plants for curing neurologic diseases, it is believed that the research in the areas of ethnomedicine and ethnopharmacology can bring auspicious results that have potential of adding importance to the very rich natural resources of Pakistan. Various phytochemicals from the above medicinal plants can be further researched under clinical trials and better drugs for treatment of neurological diseases can be obtained with outstanding results and lesser side effects. This study will help all the researchers, especially from Asian countries including Pakistan, China, Iran, India, Sri Lanka, and Bangladesh, working on plants based medicine for neurological diseases.

Conclusion
The mental illnesses are one of the major problems of the world mainly in communities presenting with poor socioeconomic conditions. In Pakistan and other countries 6 Evidence-Based Complementary and Alternative Medicine               Qutenza as Patch (179mg capsacin) [190] 4 C u r c u m i n Curcuma longa Zingiberaceae Dementia Anti-amyloid, AChEI phase II [191] 5 G a l a n t a m i n e
of this region, there is no accurate and up to date record of the neurological ailments. In order to find any treatment for these diseases, first realistic survey would be required to find out the exact percentage of various neurological diseases. Being an alarming psychiatric problem, Alzheimer opens a new area of research, affecting an enormous part of world population, but it is still untreatable. A lot of attempts have been conducted but still there is no such drug that can either slow or stop the process of Alzheimer disease. Allopathic medicines are available for psychological diseases including anxiety, depression, epilepsy, Parkison, and Alzheimer, but these are either not so effective or costly or have serious associated adverse effects. The world is full of natural medicinal resources, of which the main source is plant. We should invest money and go for systemic scientific investigations to perceive such drug candidates' form these plants, which are most efficacious, have minor side effects, and are cost friendly. For this purpose, this study is a gift for researchers who have interest to design and perform research based activities in the field of neuropharmacology by evaluating the unexplored medicinal plants mentioned here for their folkloric uses, determining its mechanistic pathways and identifying chemical constituents responsible for therapeutic effects.

Data Availability
No personal data was collected from the interviewees and therefore no such data is kept or shared in any form.

Consent
Prior informed consent was obtained from all participants before conducting interviews. This manuscript does not contain any individual person's data and further consent for publication is not required.

Conflicts of Interest
The authors declare that they have no conflicts of interest.

Authors' Contributions
Abdul Waheed Khan, Arif-ullah Khan, and Syed Muhammad Mukarram Shah designed the study, performed field work, and researched various medicinal plants articles on scientific search engines. Aziz Ullah, Muhammad Faheem, and Muhammad Saleem analyzed the data and drafted the manuscript. All authors read and approved the final manuscript.