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Neuroprotection by bromocriptine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice
D Muralikrishnan1, K P Mohanakumar
1Laboratory of Neurochemistry, Division of Pharmacology and Experimental Therapeutics, Indian Institute of Chemical Biology, Calcutta.
Abstract:
Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg i.p. twice, 16 h apart). This resulted in changes in motor performance and toxic insult of nigral neurons as evidenced by dopamine depletion in nucleus caudatus putamen. In vitro and in vivo treatment of MPTP caused the generation of hydroxyl radicals (.OH) as measured by a sensitive salicylate hydroxylation procedure. A dopamine agonist, bromocriptine (10 microM and 10 mg/kg i.p.), blocked .OH formation caused by MPTP in vitro (20 microM) and in vivo (30 mg/kg i.p.). An MPTP-induced increase in the activity of catalase and superoxide dismutase in substantia nigra on the seventh day was reduced by bromocriptine pretreatment. Bromocriptine blocked MPTP-induced behavioral dysfunction as well as glutathione and dopamine depletion, indicating its potent neuroprotective action. This study suggests that bromocriptine stimulates antioxidant mechanisms in the brain and acts as a free radical scavenger in addition to its action at dopamine receptors, thus indicating its strength as a valuable neuroprotectant.
Insights
Bromocriptine protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity by scavenging free radicals and boosting antioxidant defenses. This dopamine agonist demonstrates significant neuroprotective effects, preserving dopamine levels and improving motor function.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes Parkinsonism-like symptoms in mice.
- MPTP induces oxidative stress through the generation of hydroxyl radicals (.OH).
- Dopamine depletion in the nigrostriatal pathway is a key indicator of MPTP-induced neurotoxicity.
Purpose of the Study:
- To investigate the neuroprotective effects of bromocriptine against MPTP-induced neurotoxicity.
- To determine if bromocriptine can prevent hydroxyl radical formation and modulate antioxidant enzyme activity.
- To assess bromocriptine's impact on MPTP-induced behavioral deficits and neurochemical changes.
Main Methods:
- Mice were administered MPTP to induce neurotoxicity.
- In vitro and in vivo salicylate hydroxylation assays were used to measure hydroxyl radical generation.
- Bromocriptine was administered as a pretreatment to assess its protective effects.
- Activity of antioxidant enzymes (catalase, superoxide dismutase) and levels of glutathione and dopamine were measured.
- Motor performance was evaluated.
Main Results:
- MPTP treatment led to motor deficits, nigral neuron damage, and dopamine depletion.
- MPTP induced significant hydroxyl radical formation, which was blocked by bromocriptine.
- Bromocriptine pretreatment reduced MPTP-induced increases in catalase and superoxide dismutase activity.
- Bromocriptine prevented MPTP-induced behavioral dysfunction, glutathione depletion, and dopamine loss.
Conclusions:
- Bromocriptine exhibits potent neuroprotective actions against MPTP toxicity.
- Its neuroprotection is attributed to free radical scavenging and stimulation of endogenous antioxidant mechanisms.
- Bromocriptine's dual action as a dopamine agonist and antioxidant supports its potential as a neuroprotectant.