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Presented by: Natasha Frett

Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra Gustavo Costa, J.A. Abin-Carriquiry, Federico Dajas (2001). Brain Research Interactive. 888; 336-342. Presented by: Natasha Frett. Objective.

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Presented by: Natasha Frett

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  1. Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigraGustavo Costa, J.A. Abin-Carriquiry, Federico Dajas (2001). Brain Research Interactive. 888; 336-342 Presented by: Natasha Frett

  2. Objective • To evaluate the therapeutic action of nicotine in preventing striatal dopamine loss in lesions of the substania nigra in Parkinson’s disease.

  3. The Brain: Basal Ganglia • Found in the deep white matter of the cerebral cortex • 4 primary nuclei • The striatum (caudate nucleus, putamen, ventral straitum) • Globus pallidus ( or pallidum) • Substantia nigra (pars reticulata and pars compacta) • The subthalamic nucleus

  4. The Brain: Basal Ganglia

  5. The Brain: Basal Ganglia

  6. Parkinson’s disease • Neurological disease 1st described in 1817 by Dr. James Parkinson in his Essay on the Shaking Palsy. • Deterioration of neurons in the substantia nigra (pars compacta). - Deterioration due to defects in cellular mechanisms involving the breakdown of protein. - Causes the accumulation of debris that clogs and kills brain cells.

  7. -Reduces the amount of dopamine - Dopamine inhibits the secretion of Acetylcholine, the primary neurotransmitter to muscles. - Dopamine acts on the Nicotinic- acetylcholine receptors (nAChR) in the post-synapse - Also reduces the number of receptors

  8. Probable Causes: • National Human Genome Research Institute (NHGRI) and the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health identified an abnormal gene on chromosome 4, that maybe responsible for a small fraction of Parkinson’s disease cases.

  9. Probable Causes: • Inherited susceptibility. • Elements in the environment such as chemicals (insecticides and herbicides) induces the onset of the disease. • Viral infection • Toxic insult

  10. Tremor in resting muscles Muscular rigidity of the arms, legs and neck Bradykinesia (difficulty initiating movement) Loss of balance Depression Memory problems and dementia Speech problems Difficulty swallowing Sleep disorders Symptoms Some of the symptoms of Parkinson’s disease:

  11. Diagnosis and Treatment Diagnosis: • Familial history of Parkinson’s disease • Physical examination Treatment: • Drug therapy. (Eg. L-dopa) • Surgery

  12. Objective: Subjects: To observe the neuroprotective effects of nicotine on induced substania nigra lesions in rats. Sprague –Dawley rats (230-260 g). Housed in groups of 6 and given access to food and water. 12hr light/dark cycles Nicotine prevents striatal dopamine loss.

  13. Solutions 6-OHDA: Nicotine: Chlorisondamine: 6-OHDA, aCSF, 0.2% ascorbic acid. (-) nicotine + saline Chlorisondamine (CHL) + saline Nicotine prevents striatal dopamine loss.

  14. Methods: 6 rats were injected with similar volumes of aCSF and 0.2% ascorbic acid, for 6-OHDA control. Partial lesioning (6 g dose ) 5 groups of 8 rats were obtained and were given different nicotine at different times. Each experimental group had a control using 6-OHDA + saline Nicotine prevents striatal dopamine loss.

  15. Methods: A small hole was made in the skull and a needle attached to a syringe was lowered into substantia nigra. At 37°C, 2 l of 6-OHDA solution was injected for 4 mins in the right substantia nigra. 2 doses: 3 g/ l (6 g); 5 g/ l (10 g). Received 1mg/kg of nicotine treatments subcutaneously in differing time periods. Nicotine prevents striatal dopamine loss.

  16. Protocols

  17. 10 g dose received nicotine 4hrs before injection of 6-OHDA and 20, 44, 68 hrs after. (protocol 3)

  18. Neuro-chemical analysis • Brains were removed, sonicated in .1M perchloric acid and centrifuged at 15000g for 15mins at 4°C • Injected into a HPLC system.

  19. Results Rationale: Intranigral injections of both doses of 6-OHDA showed a decrease in dopamine levels in tissues.

  20. Results: Intranigral injections Dopamine levels as ng/g of wet weight ± S.D

  21. Results: Nicotine had neuro-protective effects which enabled the neurons to produce more dopamine.

  22. 6g of 6-OHDA and Nicotine % Dopamine in nicotine and CHL treatments

  23. 10g of 6-OHDA and Nicotine % Dopamine in nicotine treatment

  24. 6g and 10g doses of 6-OHDA

  25. Protocols

  26. Activity of Nicotine in Protocols

  27. Dopaminergic neurons synthesize neurons. • DOPAC is a metabolite of dopamine. • Increased ratios indicate an increase in dopamine turnover. This indicates increased activity in dopaminergic neurons. Note: damage is caused to nicotinic receptors.

  28. DOPAC/DA ratios

  29. DOPAC/DA ratios

  30. Neuroprotective effects of Nicotine • Increased ratios of DOPAC/DA indicates that the protective effects is linked to the nicotinic- acetylcholine receptors (nAChR). • Nicotine causes an increase in the (nAChR) However, the neuroprotective effect is due to the activation of and function of these receptors.

  31. Neuroprotective effects of Nicotine cont’d • Nicotine increases basic fibroblast growth factors which protects against neurotoxicity. • Fibroblast factor peaks 4 hrs after injection and returns to normal levels 24 or 48 hrs after injection.

  32. Conclusion • Parkinson’s disease is a neurological degenerative disease that affects transmittance of dopamine • Dopamine regulates the secretion of acetylcholine- muscle receptor • Dopamine transmittance occurs in the basal ganglia, which sends inhibitory stimuli to cerebral cortex

  33. Defects in cellular mechanisms cause the formation forms debris that clog and kill cells. • Dopaminergic neurons and Nicotinic-acetylcholine receptors are destroyed at dopaminergic terminals, reducing binding at the postsynapse. • This increases the presence of Acetylcholine and uncontrolled stimuli to muscle.

  34. Nicotine increases the amount of Nicotinic-acetylcholine receptors and increases the level of trophic factors.

  35. References: • Gustavo, C., Abin-Carriquiry, J.A., Dajas, F.(2001) Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra. Brain Research Interactive Vol 888:336-342 • Court, J.A., Martin-Ruiz, C., Graham A., Perry, E. (2000) Nicotinic receptors in human brain: topography and pathology. Journal of Chemical Neuroanatomy Vol. 20; 281-298 • Quik, M., Jeyarasasingam, G.(2000) Nicotinic receptors and Parkinson’s disease. European Journal of Pharmacology Vol. 393; 223-230 • Kandel, E.R., Schwartz, J.H. and T. Jessell (2000) Principles of neural science 4th ed. McGraw-Hill. New York

  36. Division of intramural research http://www.nhgri.nih.gov/DIR/LGDR/PARK/about_parks.html • Washington University School of Medicine http://thalamus.wustl.edu/course/cerebell.html

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