Influence of Coenzyme Q10 on Phenothiazine Induced Extrapyramidal Symptoms in Rats

Nitin M., Prasad K., Dastapur A. and Suryawanshi S.*

Department of Pharmacology, H.K.E Society’s College of Pharmacy, Sedam Road, Gulbarga – 585105, Karnataka, India.

ABSTRACT:

Single dose and multiple dose influence of, Coenzyme Q10 in chlorpromazine induced catatonia was studied in adults albino rats of either sex. The study intended to find the role of antioxidants coenzyme Q10 in controlling extrapyramidal side effects. Phenothiazine derivatives produce catatonia as an unwanted side effect when used especially for prolonged periods of time in psychiatric disorders. The catatonia was induced in albino rats using chlorpromazine in the dose of 0.9mg/200g p.o. and the degree of catatonia was recorded. Coenzyme Q10 was administered first followed by chlorpromazine after 30 minutes p.o in single dose studies. In multiple dose studies Coenzyme Q10 was administered for 8 days followed by the combination of Coenzyme Q10 and chlorpromazine on 9^th day as described above and the degree of catatonia was scored. The study reveals that coenzyme Q10 produced statistically significant reduction of extrapyramidal symptoms in both single and multiple dose studies. Thus coenzyme Q10 has beneficial effects in controlling the toxicity symptoms of phenothiazines. Since, coenzyme Q10 is used safely in the form of food supplement it can be recommended in patients who are using phenothiazine derivatives for prolonged periods of time.

KEYWORDS: Chlorpromazine, Catatonia, Coenzyme Q10, Extrapyramidal symptoms.

INTRODUCTION

Phenothiazine derivative like chlorpromazine are widely used in psychiatric disorders for sedative and tranquilizing properties. They act by inhibiting the release of dopamine. Chlorpromazine effectively treats schizophrenia, severe mania in people with bipolar disorder. Chlorpromazine binds with a variety of receptors in the central nervous system producing anticholinergic, antidopaminergic, antihistaminic, and antiadrenergic effects. Its antidopaminergic properties can cause extrapyramidal symptoms such as akathisia, dystonia, and Parkinsonism^1,2.

Catatonia is a state of immobility and unresponsiveness and in olden days was a common unwanted effect when the treatment for schizophrenia was not available. Catatonia is a syndrome of either short or long duration and is typically manifested by affective, behavioral, cognitive, and motor symptoms³.

Catatonia may be a primary idiopathic disorder or a secondary disorder. It is relatively common in academic hospital units, with 6 to 9% meeting the criteria of two or more signs for 1 day or longer. Secondary catatonia can have a sudden or a gradual onset and is often linked to neurological abnormalities (lesions, infections, epilepsy), metabolic disturbances, or can be iatrogenic⁴.

Catatonia can lead to medical complications involving every organ system. Treatable complications include dehydration and malnutrition, incontinence, and prolonged staring and reduced blinking. Immobility places the patient at risk for deep venous thrombosis (DVT) and pulmonary emboli (PE), decubitus ulcers, contractures, and infections⁵.

An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation reactions are crucial for life, they can also be damaging hence plants and animals maintain complex system of multiple types of antioxidants such as glutathione, vitamin-C and E as well as enzyme such as catalase, super oxide dismutase and various peroxidase. Low level of antioxidants or inhibition of antioxidant enzymes causes oxidative stress and may damage or kill cells. To reduce the harmful / damaging effects of free radicals, the aerobic cells have developed antioxidant defense mechanisms. An antioxidant may be considered as the scavenger of free radicals⁶.

Coenzyme Q₁₀ also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated as CoQ_10. This oil-soluble vitamin-like substance is present in most eukaryotic cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, generating energy in the form of ATP. Ninety-five percent of the human body’s energy is generated this way. Therefore, those organs with the highest energy requirements—such as the heart and the liver—have the highest CoQ₁₀ concentrations⁷.

Supplementation of Coenzyme Q₁₀ is a treatment for some of the very rare and serious mitochondrial disorders and other metabolic disorders, where patients are not capable of producing enough coenzyme Q₁₀ because of their disorder⁸.

There is some clinical evidence that supplementation with Coenzyme Q10 is beneficial in treatment of patients with congestive heart failure. It is also being investigated as a treatment for cancer, and as relief from cancer treatment side-effects^9,10. The plasma peak can be observed 2-6 hours after oral administration, mainly depending on the design of the study. In some studies, a second plasma peak was also observed at about 24 hours after administration, probably due to both enterohepatic recycling and redistribution from the liver to circulation¹¹.

The literature also reveals that phenothiazine drugs might deplete the body level of Coenzyme Q10, supplementing with phenothiazine drugs might be good idea^12,13.

MATERIALS AND METHODS:

Albino rats (Wistar strain) of either sex weighing between 180-220g were procured from central animal house M. R. Medical College, Gulbarga. After procuring, the animals were acclimatized for seven days under standard husbandry condition with 12:12 h light and dark cycle.

The animals were fed with standard diet manufactured by Amrut laboratories Pranava Agro Industries Ltd. Sangli. Water was allowed ad libitum under strict hygienic conditions. After obtaining prior permission from Institutional Animal Ethics Committee (HKECOP/IAEC/02/2008-09) the studies were performed in accordance with CPCSEA guidelines. Coenzyme Q10 and chlorpromazine were suspended in 1% gum acacia and administered.

Pure sample of chlorpromazine was a gift sample from Sun Pharmaceuticals Ind.Ltd, Silvassa, and coenzyme Q10 from Elder Health Care Ltd; Dist. Raigad. Animal feed was supplied by Amrut laboratories Pranava Agro Industries Ltd. Sangli.

Single dose studies:

The normal adult rats of either sex were selected and divided into 2 groups each containing six animals. Chlorpromazine 0.9 mg/200g was administered in group I and coenzyme Q10 5.4mg/200g + chlorpromazine was administered in group II. The severity of catatonia was observed at 0min, 30min, 1^st, 2^nd, 4^th, 6^th, 8^th, and 12^th h in control and test groups.

Group 1- Control: coenzyme Q10 suspension.

Group 2- Coenzyme Q10 followed by chlorpromazine after an interval of 30 min.

Statistical analysis: Results were expressed as mean ± SEM. The difference among means was analysed by unpaired Student’s t-test.

Multiple dose studies

Studies with multiple dose administration were planned based on the result of single dose studies. In multiple dose studies coenzyme Q10 was administered for 8 days in the dose of 5.4mg/200g p.o. and on 9^th day combination of chlorpromazine and coenzyme Q10 was administered as described earlier. The degree of catatonia was scored. Keeping the experimental protocols identical as in single dose studies.

Group 1- Control: coenzyme Q10 suspension.

Group 2- Coenzyme Q10 followed by chlorpromazine after an interval of 30 min.

Table 1: Catatonic response of chlopromazine

Sr. No.	Treatment	Body wt. ( g )	Dose mg/kg	Degree of catatonia
				0min	30min	1h	2h	4h	6h	8h	12h
1.	CPZ	210	0.94	0	1	1.5	2.5	2.5	3.5	2	0
2.		180	0.81	0	0.5	1	1.5	0.5	2.5	1	0
3.		190	0.85	0	0.5	1	2	2.5	1.5	0.5	0
4.		220	0.99	0	1	1.5	2	3	2.5	1.5	0
5.		200	0.90	0	0.5	1.5	1.5	2.5	1.5	0.5	0
6.		190	0.85	0	0.5	1.5	2.5	3.5	1.5	0.5	0
Avg. ± SEM				0±0	0.7±0.11	1.3±0.11	2.0±0.18	2.4±0.42	2.2±0.33	1.0±0.26	0

n = 6

Table 2: Catatonic response of CPZ in the presence of CO-Q10

Sr. No.	Treatment	Body wt. ( g )	Dose mg/kg	Degree of catatonia
				0min	30min	1h	2h	4h	6h	8h	12h
1.	CO-Q-10+CPZ	180	4.05+0.81	0	0.5	1.5	2.5	3.5	3.5	2.5	0
2.		200	4.5+0.9	0	1	2.5	2.5	3.5	3.5	2.5	0
3.		210	4.72+0.94	0	0.5	0.5	1.5	0.5	0.5	0	0
4.		220	4.95+0.99	0	0.5	1	1.5	2.5	1	0	0
5.		190	4.2+0.85	0	0	0.5	1.5	0.5	0.5	0	0
6.		190	4.2+0.85	0	0	0.5	1.5	2	1.5	1.5	0
Avg. ± SEM				0±0	0.4±0.15	1.08±0.33	1.83±0.21	2.1±0.55*	1.8±0.57	1.08±0.51	0±0

n = 6, *P<0.05

Table 3: Catatonia of CPZ after multiple dose administration with CO-Q-10

Sr. No.	Treatment	Body wt. ( g )	Dose mg/kg	Degree of catatonia
				0min	30min	1h	2h	4h	6h	8h	12h
1.	CO-Q-1O +CPZ	200	5.4+0.9	0	0	0.5	0.5	1	0.5	0	0
2.		190	5.13+0.85	0	0	0.5	1.5	1.5	0.5	0	0
3.		210	5.67+0.94	0	0.5	1.5	1.5	1.5	0.5	0	0
4.		220	5.94+0.99	0	0.5	1.5	1.5	1.5	0.5	0	0
5.		190	5.13+0.85	0	0.5	1	0	0	0	0	0
6.		180	4.86+0.80	0	0	0.5	1	1.5	0	0	0
Avg. ± SEM				0±0	0.25±0.1*	0.9±0.2	1±0.26*	1.2±0.25*	0.3±0.11**	0±0	0±0

n = 6, *P < 0.05, **P < 0.01

RESULTS:

The result of single dose studies indicated a reduction in catatonia score as given in table and represented graphically in figures 2 and 3. The results are statistically significant with P<0.05 and P< 0.01.

Graph: 1 Catatonic response of chlorpromazine

CPZ = Chlorpromazine, n = 6

Graph: 2 Catatonic response of CPZ in the presence of CO-Q 10

CO-Q-10 = Co-enzyme Q10, CPZ = Chlorpromazine, n= 6

The degree of catatonia in chlorpromazine induced group 0.9mg/200g is shown in graph and table-1. The onset of action was within 30 min of the administration of chlorpromazine, and the animals recovered within 12 hour with the peak effect at 4^th hour with maximum catatonic score of 2.4.

A reduction in catatonia was observed as shown in graph and table -2. The onset of action was 30 min, the animals recovered within 12 hour with peak effect observed at 2^nd hour with maximum catatonic score was 2.1.

The animals also recovered quickly compared to control and single dose studies as shown in figure-3 and table no.-3. The degree of severity was 1.2 compared to control score of 2.4.

Graph: 3 : Catatonia of CPZ after multiple dose administration with CO-Q 10

CO-Q-10 = Co-enzyme Q10, n = 6

DISCUSSION:

Chlorpromazine is the oldest typical antipsychotic. Catatonia produced due to chlorpromazine is life threatening at the intensive psychiatric care unit. It effectively treats schizophrenia, severe mania in people with bipolar disorder. Chlorpromazine works on a variety of receptors in the central nervous system. Its antidopaminergic properties can cause extrapyramidal symptoms such as akathisia (restlessness), dystonia, and Parkinsonism. Chlorpromazine can cause tardive dyskinesia, which is sometimes irreversible.

Coenzyme Q10 is well known for its antioxidant activity. Coenzyme Q10 acts as a reducing agent to reverse oxidation. Literature reveals that, high doses of Coenzyme Q10 may have "protective effects" on lead-induced nerve and muscle abnormalities especially in smokers¹⁴.

As there are more free radicals (Reactive oxygen species) in the body versus antioxidants available, a human body is under oxidative stress. Oxidative stress induced diseases encompass cardiovascular diseases, hypertension, chronic inflammatory diseases and diabetes. The plasma ascorbate concentration in oxidative stress patient (less than 45 µmol/L) measured is lower than healthy individual (61.4-80 µmol/L)^15,16.

Antioxidant enzyme superoxide dismutase (SOD), catalase and glutathione peroxidase help to catalyse the reduction of oxidants in a cell and exert their effects by counteracting oxidative processes that contribute to the cause of the chronic diseases. The reduction in catatonia by coenzyme Q10 can be due to its antioxidant activity. The research indicates that coenzyme Q10 can be recommended as adjuvant therapy in patients who are using chlorpromazine for prolonged periods of time.

ACKNOWLEDGEMENT:

The authors are thankful to Elder Health Care Ltd; Khalupur, Dist. Raigad for gift sample of Coenzyme Q10 and also thankful to Sun Pharmaceuticals Ind. Ltd, Silvassa for gift sample of chlorpromazine and the authorities of HKES’S college of pharmacy for providing the facilities.

REFERENCES:

1) Rang HP, Dale MM, Ritter JM, Moore PK. Antipsychotic drugs. Pharmacology, Churchill Livingstone Robert Stevenson House Edinburgh EH 1 3AF. 1999; 547-548.

2) Tripathi KD. Drugs used in mental illness: Antipsychotics and antianxity drugs. Essentials of Medical Pharmacology, Jaypee Brothers medical publishers (P) LTD, New Delhi 2008; 6^th Ed: pp.423-433.

3) Reddick B, Stern TA. Catatonia, neuroleptic malignant syndrome,and serotonin syndrome. In:Stern TA, Herman JB, eds. Massachusetts General Hospital Psychiatry Update & Board Preparation, . New York, NY: McGraw-Hill; 2004 :( 2) 217-224.

4) Hawkins JM, Archer KJ, Strakowski SM, et al. Somatic treatment of catatonia. Int J Psychiatry Med 1995; 25:345-369.

5) Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci 2001; 251(Suppl. 1):8–13.

6) Satyanarayan U, Chakrapani U. Free radicals and antioxidants. Essentials of Biochemistry, Books and Allied (P) Ltd. Kolkata-700010, 2^nd Ed:pp. 351-354.

7) Hasan MY, Alshuaib WB, Singh S, Fahim MA. "Effects of ascorbic acid on lead induced alterations of synaptic transmission and contractile features in murine dorsiflexor muscle". Life Sci. 2003; 73 (8): 1017–25.

8) Huang J, Agus DB, Winfree CJ et al. "Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke". Proceedings of the National Academy of Sciences 2001; 98 (20): 11720–4.

9) Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta 1271: 195-204, 1995

10) Berbel-Garcia, A. et al. "Coenzyme Q 10 improves lactic acidosis, stroke like episodes, and epilepsy in a patient with melas". Clinical Neuropharmacology 2004; 27:187–191.

11) Damian MS. et al. "Coenzyme Q10 Combined With Mild Hypothermia After Cardiac Arrest". Circulation, American Heart Foundation 110: 3011–3016.

12) Folkers K. Basic chemical research on Coenzyme Q10 and integrated clinical research on therapy of diseases. In Lenaz G, ed. Coenzyme Q. New York : John Wiley and sons, 1985.

13) Kishi T, Makino K, Okamoto T, et al. Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by Coenzyme Q. In: International of Symposium on Coenzyme Q. Biomedical and clinical aspects of Coenzyme Q. New York, NY: Elsevier Science Publishing Co; 1980(2): 139-157.

14) Satoh K, Sakagami H. Effect of metal ions on radical intensity and cytotoxic activity of ascorbate. Anticancer Res 1997; 17:1125–1129.

15) Eipper BA, et al. "Peptidylglycine apha-amidating monooxygenase: a multifunctional protein with catalytic, processing,and routing domains”. Protein Sci. 1993; 2 (4): 489–97.

16) Englard S, Seifter S. "The biochemical functions of ascorbic acid". Annu. Rev. Nutr. 1986; 6: 365–406.

Received on 11.03.2010

Accepted on 19.04.2010

© A&V Publication all right reserved

Research J. Pharmacology and Pharmacodynamics. 2(3): May-June 2010, 248-251