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8. Neurodegenerative disease.docx

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Kristin Hillman

Week 8 – Parkinson‟s disease 8/23/2013 2:29:00 PM Neurodegenerative disease: Term used to describe a range of conditions which primarily affect the neurons in the human brain. These diseases are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells.  eg. o Alzheimer‟s o Parkinson's o Huntington's o Amyotrophic Lateral Sclerosis  Progressive and irreversible loss of neurons  Doesn‟t stop…once lost, very very very hard to get back  Selective vulnerability within neuronal populations  Available therapies treat symptomology; currently no available cures Parkinson’s disease:  James Parkinson o First to characterize  Cardinal features (x4): o Bradykinesia (slow movement) o Muscle rigidity (particularly starting in small joints, hard to move) o Tremor at rest (key feature of P's disease) o Impaired balance and gait (standing/posture and walking – shuffle)  Primarily a movement disorder  But also sensory, cognitive and behavioural changes  Progressive, 5-10 years until rigid, akinetic state – have to go into home and someone else has to care for you  Book of interest: Jonathon Franzen, The Corrections  Charactersitic pathology (inside the brain):  70-80% loss of DA neurons in substantia nigra (key feature) o Very specific area o Substantia nigra = black stained substance – image = left side is parkinson‟s patient, right side is normal.  Lewy Bodies appear o aggregates of alpha synuclein protein Overview = DA tracts:  4 major tracts o 1. Nigrostriatal  Focus on this today because this is the area with substantia nigra  Basal Ganglia = critical for gating movement (main feature)  Motor cortex initiates movement, Cerebellum and BG help fine tune that movement to get it refined o 2. Mesolimbic/accumbens o 3. Mesocortical o 4. Tuberoinfundibular (hormonal pathway) Cause of PD (aetiology)  No known cause (idiopathic) o There are lots of theories…  Genetic predisposition?  Free radical damage?  Environmental risk factors?  Excitotoxicity?  Minority of cases have been found to have genetic basis – but this is minority…we don‟t know about majority  “Parkinsonaian” movement disorders can also be drug-induced  People went out to get high on MPPP, but instead they killed off all their DA neurons…  Today, MPTP is used in laboratory as standard “Parkinsonian model” Treatment Approach  If we don‟t know cause, how do we treat? o We don‟t know what causes PD but we do know what PD is characterized by progressive loss of DA neurons in the substantia nigra  try to restore DA function in substantia nigra  Maybe we could just administer them DA??  Problem with this = BBB (DA doesn‟t cross the BBB) o If you cant give DA, maybe you could give a precursor of it…tyrosine  DOPA  dopamine  Medications have radically altered prognosis for PD  Mobility for many years  Significantly increase in life expectancy DA  Synthesis o derived from tyrosine  DOPA  dopamine  Vesicular loading into pre-synaptic vesicles via VMAT-2  Receptors:  D1, D5 = metabotropic (Gs – excitatory)  D2, D3, D4 = metaboltropic (Gi, g(k+) – inhibitory)  Clearance  Pre-synaptic transporter (DAT) + ENT and OCT  Also have enzymatic clearance MAO-B (specific one for DA) and COMT  if we are going to design drugs to increase DA in brain…  start with synthesis: o could overload system with tyrosine? Or even DOPA? – which would turn into DA  Levodopa (L-dopa)  Pro-drug – has to be metabolized to turn into something and be active  Mechanism of action: o  Precursor for dopamine  ROA o oral  Absorption o good, uses transporter, best on empty stomach  Distribution o Crosses BBB using transporter  Metabolism o Converted to DA by AA decarboxylase o Converted to inactive metabolite by MAO-B + COMT o T1/2 = 1-3 hours  What is major problem? o Almost all of the L-dopa is metabolized in the peripheral before it crosses brain (99%) – it is converted to DA o Excess peripheral DA causes multitude of side effects o e.g. hypotension, arrhythmias, nausea, vomiting  Carbidopa  use one of these drugs with L-dopa so it inhibits peripheral synthesis of DA…L-dopa is forced to go into brain and then it can turn into DA…  don‟t want these into brain so they are specifically designed to not cross the BBB  Talcapone  Inhibits peripheral COMT o L-dopa is used with at least one of these drugs… L-dopa  Dosing regimes: o While L-dopa continues to be the standard therapy for PD, it loses efficacy with long-term use o "On/off” phenomenon  Referring to „wearing off‟ (this is just a tolerance issue, unavoidable with L-dopa)  In early phases: o Medications can almost completely reverse clinical presentations  In later phases: o Medications provide 1-2 hours mobility, then wear off o Increasing the dose/frequency = dyskinesia, psychoses o Sustained release concentrations (Sinemat CR) used in attempt to reduce on/off Treatement of PD?  Pharmacologically exploiting the synthesis step of the DA system was an idea strongly supported by the neurologist Oliver Sacks  Treatments weren‟t without shortcomings: o They do wear off (ON/OFF) – tolerance thing.. o psychosis o Greatest benefit  Use L-dopa therapy in combination with enrichment therapy (get up and start moving around and dance etc.)  When you do use drug therapy, it is important to combine it with enrichment therapy to get patient moving Release?  What drugs increase release of DA? o Amphetamines (promote release of DA and NE)  Would you use amphetamines for treating PD?  No – they are highly reinforcing…  Particularly with the reward pathways…they can become highly addicted  Could never use them clinically because they are a drug of abuse Post-synaptic receptor?  DA receptor agonists: o 2 advantages:  1. Doesn‟t require functional neurons to convert L-dopa to DA  If put L-dopa into system, you need neurons to convert this…this strategy does work, but as you start to lose more and more neurons you start to lose the enxymes that convert it – next step is to use these DA receptor agonists o 2. Act longer – so less fluctuations in plasma levels  Longer half-lives than L-dopa (12-14 hours vs. 3 hours)  Bromocriptine = example of DA receptor agonist  Disadvantages of these drugs: o Older agents marginally effective, side effects however  Hallucination, psychoses, nausea, excess fatigue, hypotension Clearance?  Last level you could target…  Would want to reduce clearance = block DAT or MAO, COMT o What drug could be used to reduce clearance of DA?  Cocaine…blocks DAT  Ritalin – also blocks transporter  Drugs like these in theory could work to reduce clearance of DA, but would you use these…no Selegiline: th  Drug that is used on 4 mechanism (clearance)  Mechanism of action o Selectively inhibits MAO-B enzyme  MAO-B degrades dopamine…selegiline inhibits this  Metabolic intermediates include amphetamine (force the release of DA)  Good or bad thing? o  Inhibiting enzyme, so in early s
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