Possible involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant activity of berberine chloride.
Berberine is an isoquinoline alkaloid isolated from Berberis aristata, a major herb widely used in Indian and Chinese systems of medicine. Berberine possessed a wide range of biological activity including antidiarrheal, antimicrobial, anti-inflammatory effects and some central nervous system activity as well. The present study was designed to explore the antidepressant activity and its possible mechanism of action. Further, the involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of berberine chloride was investigated. The antidepressant activity was assessed in forced-swim and tail-suspension tests. Total immobility period was recorded during a six-min test. Berberine (5-20 mg/kg, i.p.) produced a reduction in immobility period in both the tests. When berberine (5 mg/kg, i.p.) was co-administered with other antidepressant drugs, it enhanced the anti-immobility effect of subeffective doses of imipramine (2 mg/kg, i.p.), desipramine (5 mg/kg, i.p.), tranylcypromine (4 mg/kg, i.p.), fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) in forced-swim test. However, berberine did not modify the effects of mianserine (32 mg/kg, i.p.) or trazodone (2 mg/kg, i.p.), the two atypical antidepressant drugs. The neurochemical analysis revealed that berberine (5 mg/kg, i.p.) increased the levels of norepinephrine, serotonin or dopamine in the mouse whole brain. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced-swim test was prevented by pretreatment with L-arginine (750 mg/kg, i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg, i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of berberine (2 mg/kg, i.p.). In addition, treatment of mice with methylene blue (10 mg/kg, i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of berberine (2 mg/kg, i.p.) in the forced-swim test. Furthermore, the reduction in the immobility period elicited by berberine (5 mg/kg, i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg, i.p.) [phosphodiesterase 5 inhibitor]. The various modulators and their combination with berberine did not produce any changes in locomotor activity. Our findings demonstrated that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin or dopamine) and further, the antidepressant-like effect of berberine in the forced-swim test involved an interaction with the L-arginine-NO-cGMP pathway.
Kulkarni
Shrinivas K
SK
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India. skpu@yahoo.com
Dhir
Ashish
A
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001599:Berberine / Q000008:administration & dosage / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019417:Hindlimb Suspension / Q000009:adverse effects; D007191:Indazoles / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000068677:Sildenafil Citrate; D013315:Stress, Psychological / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013550:Swimming; D013997:Time Factors
D000928:Antidepressive Agents; D007191:Indazoles; D018377:Neurotransmitter Agents; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D001599:Berberine; D009569:Nitric Oxide; D001120:Arginine; D000068677:Sildenafil Citrate; D006152:Cyclic GMP; C080122:7-nitroindazole