INTRODUCTION:

Around 80% of the population in developing countries still depends on the traditional medicines for their primary health care needs and higher plants are the main source of their medicinal preparations. As per the data from global survey, it was found that at least 130 plants were used in modern medicine.

Plants have provided useful drugs to mankind for their health care and other needs. The efforts to combat the disease for which there is no satisfactory solution as yet,

should be continued relentlessly. Hopefully, plant kingdom will help us in the discovery of new drugs useful for the alleviation of human illness¹.

The human brain is the single most important organ of the human nervous system. Humans and other species are distinguished by the functions of their brain and physiology. Disorders of the brain’s function (anxiety, epilepsy, depression, dementia) are the major concern of human society. WHO defines “health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”, it is also suggested that there is no health without mental health.

Sixty to seventy million people in India have been suffering from mild to severe mental disorders and treatment has been given for their condition. From different literatures it is estimated that 22% of individual having one or more mental or behavioral disorders associated during their life time. Among all the diseases of human being, it is estimated that approximately 12% of psychiatric disorders are the global disease burden in nowadays. It is assumed that it may likely to be increase upto 15% by 2020. It is also said that the progress rate of mental illness by 2025 may be catched up with heart disease or may even cross the figure. Since it is considered as the biggest global health concern².

Most prevalent biogenic amines present in the nervous system are norepinephrine, epinephrine, dopamine and 5-Hydroxytryptamine. The first three monoamines are called as catecholamines because they have an amino group and catechol ring nucleus. A brief description of various neurotransmitters and their receptors present in the brain is as follows:

Norepinephrine [NE]:

NE secreting neurons (noradrenergic neurons) synthesize dopamine and an extra enzyme, dopamine beta hydroxylase, which converts dopamine into norepinephrine or epinephrine. Action of these transmitters is terminated by reuptake. Presynaptic receptors modulate releaseand synthesis³.

Location:

Relatively large amount of norepinephrine is found inside the hypothalamus, some portions of limbic systemincluding centralamygdala nucleus and the dentate gyrus of the hippocampus.

Receptors:

Major subtypes are alpha1, alpha2 and betareceptors. Bothofthese receptors act via G-protein coupled mechanism.

Function:

NE plays important role in cycle of arousal, deep sleep, dreaming and regulation of mood.

Epinephrine [E]:

It is also called as Adrenaline. Adrenergic neurons produces norepinephrine and an additional enzyme phenyl ethanolamine-N-methyl transferase that synthesizes epinephrine from norepinephrine.

Location:

Neurons with epinephrine are found in the medullary reticular formation and make limited connections to a few pontine and diencephalic nuclei, eventually coursing as far rostrally as the paraventricular nucleus of the dorsal midline thalamus.

Receptors:

Epinephrine acts on both alpha (alpha1 and alpha 2) and beta (beta1 and beta2) receptors.

Function:

Epinephrine is released into the blood from adrenal medulla.

5-Hydroxytyraptamine (5-HT) (Serotonin):

5-HT is indolamine that belongs to a wider category of neurotransmitters known as monoamines. Even though serotonin is a very important neurotransmitter, only about 1-2% of the body’s serotonin is found in the brain. Serotonin synthesis occurs with the amino acid tryptophan. Efficient transporters terminate the action of 5-HT and it is degraded intracellularly by monoamine oxidase⁴.

Location:

Tryptaminergic neurons are found in nine nuclei present in or adjacent to the midline (raphe) regions of the pons and upper brainstem, corresponding to well defined nuclear ensembles.

Receptors:

Molecular biological studies have identified around 14 distinct mammalian 5- HT receptor subtypes. The major receptors include 5-HT1, 5-HT2 and 5-HT3 receptor. The 5-HT1 and 5-HT2 classes of receptors are both G-protein coupled receptors with seven transmembrane spanning domain motif, while 5-HT3 class is a ligand gated ion channel receptor.

Function:

5-HT is involved in control of basic activities such as eating, sleep, arousal, control of pain, sensory perception, temperature regulation and control of mood. Serotonin also plays a role in memory function.

Dopamine [DA]:

It is a monoamine neurotransmitter. Dopamine however, is a catecholamine. Scientific importance of dopamine is usually based on the fact that it is involved in the brain’s reward circuit. For this reason dopamine is strongly implicated in the connection with addicting substances. Dopamine synthesis is initiated when the aminoacid tyrosine enters dopaminergic neurons⁵.

Location:

More than half of the catecholamine in CNS is dopamine, and large amounts are found in basal ganglia, the nucleus accumbent, the olfactory tubercle, the central nuclei of amygdalate median eminence and restricted regions of the frontal cortex.

Receptors:

Five subtypes of dopamine receptors; D1, D2, D3, D4 and D5 have been identified. The D1 and D2 dopamine receptors are pharmacologically distinct, displaying differing affinities not only for endogenous ligand dopamine, but also for several other compounds. D₂dopamine receptors are involved in the pathophysiology of schizophrenia and Parkinson’s disease.

Function:

The principal effects of the dopaminergic systems involve movement and the internal reward system. The nigrostriatal system impacts the areas of the brain which control the voluntary movement. Dopaminergic neurons, are active during emotional responses, addictive behaviours and pleasurable experiences.

Overview of CNS Disorders:

The discrepancy in the intricate balance between neurotransmitters, neuro modulators, neuro-hormones, and neurotrophic factors leads to pathophysiological consequences giving rise to various CNS disorders. Anxiety, depression and epilepsy are considered as the most common central nervous system ailments (CNS) affecting large number of human population worldwide⁶.

Anxiety:

Fear, as described by Walter Cannon in the 1920s, is generally viewed as a reaction to danger, however anxiety is a feeling of fear that is exaggerated response to any real threat. When anxiety is persistent, it is termed as generalized anxiety disorder. When it is manifested as sudden and repeated episodes of panic, it is called panic disorder. Anxiety is often a prominent manifestation of depression, trauma-related stress disorders, and certain personality disorders, such as obsessive-compulsive disorder.

Neurochemicals modulating Fear and anxiety:

The neuroan atomical structures that support fear and anxiety behaviour are modulated by a variety of neurotransmitter systems. These include the peptidergic neurotransmitters, CRH, neuropeptide Y (NPY), and substance P, the monoaminergic transmitters, NE, serotonin (5-hydroxytryptamine or 5-HT), and dopamine (DA), and the amino acid transmitters, GABA and glutamate. The neurotransmitter systems that have been best examined in association with responses to stress or threat involve the HPA axis and the central noradrenergic system. These neurochemical systems performs important adaptive functions in responding to threat or stress, by increasing vigilance, modulating memory, mobilizing energy stores, and increasing cardiovascular function⁷.

These biological response to threat and stress can be maladaptive if they are chronicallyor inappropriately activated. Additional neurochemical systems that play essential role in modulation of stress response and emotional behaviour include the central GABAergic, serotonergic, dopaminergic, opiate, and NPY systems.

MATERIALS AND METHODS:

Plant Material Collection:

Toxicodendron succedaneum leaves were gathered from the local areas of Hyderabad, Telangana. The plant specimen was authenticated by Dr A Vijaya Bhasker Reddy, Department of Botany, University College of Science, Osmania University, Hyderabad with the voucher no. OUAS-127.

After being cleaned and chopped into small pieces, the plant material was allowed to air dry at room temperature in the shade before being roughly ground into powder in a mixer. The powdered material was used for the extraction procedure.

Preparation of plant extracts:

1. Preparation of Aqueous Extract:

Toxicodendron succedaneum fresh leaves gathered were rinsed with tap water and shade dried. To prepare the leaves extract, 200g of finely chopped leaves were added to a 250ml beaker along with 200ml of water. Following thorough mixing, the material was boiled for four to five hours at 80 -100^oC. Whatmann filter paper was used to further filter the extract. Boiling the filtrate produced a concentrated residue. The concentrated product was utilized for additional experiments to verify the activities, later it was packed in sample covers and kept at room temperature⁸.

2. Preparation of Alcoholic Extract:

Toxicodendron succedaneum fresh leaves were gathered and given a quick rinse with tap water. To make the leaves extract, 20grams of finely chopped leaves were added to a 250ml beaker along with 200ml of alcohol. After thoroughly mixing the ingredients, the mixture was cooked for four to five hours at between 50 and 60^oC. Whatman filter paper was used to further filter the extract. Boiling the filtrate produced a concentrated residue. The concentrated product was utilized for additional experiments to verify the activities, later it was packed in sample covers and kept at room temperature.

Phytochemical investigation of alcoholic extract of Toxicodendron succedaneum^9-11

S. No.	Phytoconstituents	*Toxicodendron succedaneum*
S. No.	Phytoconstituents	Aqueous extract	Alcoholic extract
1	Alkaloids	+	+
2	Flavonoids	+	+
3	Phenolic compounds	+	+
4	Tannins	+	-
5	Glycosides	+	+
6	Aminoacids	+	+
7	Terpenoids	+	+
8	Anthroquinones	-	+
9	Carbohydrates	+	+
10	Lipids	+	+
11	Saponins	-	-

‘+’ Indicates Presence, ‘-’ Indicates Absence

Preparation of extracts^12-16:

Toxicodendron succedaneum extracts, both aqueous and alcoholic, suspended in water with 3% v/v Tween-80 solution.

For the purpose of experimentation, all medications were taken orally. When necessary, extract preparations were made each time. For every animal, the dosage of the medications was maintained at 10ml per kg.

Experimental design:

Animals were divided into 4 groups of six rats each

Group I - Control group-distilled water (1ml, p.o).

Group II - Standard group - Diazepam (10mg/kg, i.p).

Group III -Test group - aqueous extract of Toxicodendron succedaneum (200mg/kg p.o).

Group IV- Test group - alcoholic extract of Toxicodendron succedaneum (200mg/kg p.o).

Screening for Anxiolytic Activity^17-20:

Antianxiety activity of Toxicodendron succedaneum:

By two different methods the anxiolytic activity was determined.

1. Elevated Plus Maze Test:

The anxiolytic properties of the Toxicodendron succedaneum leaves aqueous and alcohol solvent soluble fraction were investigated at a concentration of 200mg/kg. The alcoholic and aqueous extracts of T. succedaneum leaves, administered at a concentration of 200mg/kg p.o., substantially enhanced the number of entries and duration of time spent in the open arm in the EPM. The amount of alcohol and water extracts of T. succedaneum that had antianxiety effects at 200 mg/kg p.o. was similar to the amount of diazepam that had the same effect at 10mg/kg i.p.

Screening of antianxiety activity of ethanolic and aqueous extracts of Toxicodendron succedaneum leaves by Elevated Plus Maze.

Groups

Dose

(mg

/kg)

No. of entries in open arm(M±SEM)

Average time spent (sec±SEM)

Open Arm

Closed Arm

Open Arm

Closed Arm

Control

2.37±

1.27^*

2.49.10

±1.59^*

30.13±

8.06^*

266.46±

21.48^*

Diazepam

10 (i.p)

4.23±

0.67

4.03±

1.45

26.89±

12.48

170.56±

30.66

Aqueous

extract

200 (p.o)

3.97±

0.89^**

3.12±

1.46^**

30.56±

11.53^**

150.22±

22.38^*

Alcoholic extract

200 (p.o)

3.54±

1.89^**

2.99±

1.74^**

32.16±

1.76^**

162.24±

24.67^**

Values are expressed as mean ±SEM ^**p<0.01, ^*p<0.05 when compared to Standard group. One-way ANOVA followed by Dunnett’s test

In contrast to the standard and negative control group, mice given an aqueous and alcohol soluble fraction at a dosage of 200mg/kg body weight spent more time in the open arm of the EPM device throughout the experiment. In addition, they spent less time in the closed arm of the EPM device than the normal and negative control groups did.

Locomotor activity:

Using an actophotometer experiment, the anxiolytic properties of the Toxicodendron succedaneum leaves aqueous and alcohol solvent soluble fraction were investigated at a dosage of 200mg/Kg.

Elevated Plus Maze

After one hour, diazepam (10mg/kg i.p.) showed a 70.0% reduction in locomotor activity, which is highly significant (P<0.001) when compared to the control. In contrast, the doses of Aqueous and Alcoholic extracts of leaves (200mg/kg i.p.) showed dose-dependent decreases in locomotor activity, with 78.3% and 75.8%, respectively, when compared to standard. The values are extremely significant (P<0.000).

Effect of aqueous and alcoholic extracts of Toxicodendron succedaneum on Locomotor activity.

S. No	Groups	Dose (mg/ kg)	Locomotor activity (scores) in10 min
S. No	Groups	Dose (mg/ kg)	Before	After	% change in activity
1.	Control	-	246.13± 25.05	--	---
2.	Diazepam	30	271.33± 35.13	81.34± 9.70	70.1
3.	Aqueous	200	364.22± 33.06^**	79.06± 8.27^**	78.2
4.	Alcoholic	200	285.61± 26.19^**	69.05± 9.79^**	75.7

The values are shown as mean ± SEM**p<0.01,*p<0.05, in relation to the reference group.

Dunnett's test is performed after a one-way ANOVA, and the results are reported as means ±SEM. Utilizing a one-way analysis of variance, differences in mean values across groups were examined (ANOVA). For statistical significance, p<0.05 was used.

RESULTS AND DISCUSSION:

At a dosage of 200 mg/kg, mice in the elevated plus maze apparatus spent a considerably higher amount of time in open arms and made more entries than in the control group when exposed to aqueous and alcoholic extracts of Toxicodendron succedaneum. This resulted in anti-anxiety effects. Flavonoids and tannins were found in aqueous and alcoholic extracts using phytochemical screening. Numerous studies have shown the anti-anxiety properties of flavonoids. Moreover, flavonoids anxiolytic action has been linked to their impact on benzodiazepine receptors and the central nervous system. Thus, the anti-anxiety effect of Toxicodendron succedaneum may be attributed to flavonoids found in both alcoholic and aqueous extracts. Any of these phytochemicals potential binding to GABA_A-BZD complex might be mechanism behind the anxiolytic effects of extracts. This is corroborated by the discovery that flavones bind to the GABA_A receptor's high affinity BZD region. Flavones, which are also present in T. succedaneum, may be the source of its anxiolytic properties. Therefore, the anxiolytic impact of aqueous and alcoholic extracts may be attributed to their combined aminergic potentiating effect, effects on serotonergic transmission, or actions on GABAergic transmission.

Naturally occurring motor activity is regarded as a measure of alertness and maybe useful in verifying the overall depressive effects of any medication. The degree of the CNS's excitability may be determined by the reduction in motor activity, which may be connected to the drowsiness brought on by CNS depression. Nevertheless, it was discovered in the current investigation that the aqueous and alcoholic extracts had less of an impact on the Actophotometer’s locomotor activity.

Phytochemicals potential binding to the GABA_A-Benzodiazepines complex might be a mechanism behind the anxiolytic effects.

CONCLUSION:

Phytochemical analysis of various parts of T. succedaneum showed a vast number of bioactive compounds. The pharmacological potential of T. succedaneum reviewed here may be due to several bioactive compounds reported in the plant. However, only a few studies evaluated the pharmacological potential of the plant. Due to the presence of chemical constituents like flavonoids, glycosides, terpenoids and amino acids showed significant anxiolytic activity. Rats in an elevated plus maze were used to assess the extracts anti-anxiety properties. The Elevated Plus Maze Test revealed a substantial increase in the mean number of entries and time spent in open arms for both aqueous and alcoholic extracts (200mg/kg). Rat’s locomotor activity was shown to be less affected by both alcoholic and aqueous extracts (200mg/kg) according to the Actophotometer Test.

A case study was reported further based on the type of Anxiolytics and Antidepressants- In Terms of Efficacy, Quality of Life and Cost Analysis In a Tertiary Care Hospital^21,22.

Therefore, further research is needed to confirm its medicinal uses for developing herbal formulations/drugs through clinical studies, which help to advocate this species as a potential herbal drugs.

CONFLICT OF INTEREST:

There is no conflict of interest.

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10. Trease GE, Evans WC. Pharmacognosy. 15^th ed. Saunders Publishers: London; 2002.

11. Sofowora EA. Screening plants for bioactive agents. In: Medicinal plants and traditional medicinal in Africa. 2^nd ed. John Wiley and Sons. London; 1993.

12. C. P. Khare. Rhus succedanea Linn. in Indian Medicinal Plants: An Illustrated Dictionary, New York, NY: Springer, 2007, 1-1.

13. S. K. Bhattacharjee, Handbook of Medicinal Plants, vol. 1. Jaipur: Pointer Publishers, 2004.

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16. Sathasivampillai SV, Rajamanoharan PRS, Munday M, and Heinrich M. Plants used to treat diabetes in Sri Lankan Siddha Medicine – An ethno pharmacological review of historical and modern sources. J Ethnopharmacol. 2017; 198: 531–599.

17. Mora S., et al. The hydroalcoholic extract of Salvia elegans induces anxiolytic- and antidepressant-like effects in rats. Journal of Ethnopharmacology. 2006; 106(1): 76-81.

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20. Krithikar, K.R. and Basu B.D. Cassia occidentalis Indian Medicinal Plants II edition, 1999; 860.

21. Kingston R, Shivakumar Swamy, Arihara Sivakumar. Assessment of Prescribed Class of Anxiolytics and Antidepressants- In Terms of Efficacy, Quality of Life and Cost Analysis In a Tertiary Care Hospital. Research J. Pharmacology and Pharmacodynamics. 2009; 1(1): 39-42.

22. Thamarai Selvi P, Senthil Kumar M, Rajesh R, Kathiravan T. Antidepressant activity of ethanolic extract of leaves of Centella asiatica. Linn by in vivo methods. Asian J. Res. Pharm. Sci. 2012; 2(2): 76-79.

Received on 17.05.2024 Revised on 11.09.2024

Accepted on 28.11.2024 Published on 18.04.2025

Available online from April 22, 2025

Asian J. Res. Pharm. Sci. 2025; 15(2):117-122.

DOI: 10.52711/2231-5659.2025.00018

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Epinephrine [E]:

It is also called as Adrenaline. Adrenergic neurons produces norepinephrine and an additional enzyme phenyl ethanolamine-N-methyl transferase that synthesizes epinephrine from norepinephrine.

5-Hydroxytyraptamine (5-HT) (Serotonin):

5-HT is involved in control of basic activities such as eating, sleep, arousal, control of pain, sensory perception, temperature regulation and control of mood. Serotonin also plays a role in memory function.

Dopamine [DA]:

Overview of CNS Disorders:

Anxiety:

Neurochemicals modulating Fear and anxiety:

‘+’ Indicates Presence, ‘-’ Indicates Absence

Preparation of extracts12-16:

Experimental design:

Screening of antianxiety activity of ethanolic and aqueous extracts of Toxicodendron succedaneum leaves by Elevated Plus Maze.

Locomotor activity:

Preparation of extracts^12-16: