L17 Parkinson's Disease PDF

L17 Parkinson’s Disease and its Treatment 2 Learning Outcomes After this lecture and appropriate reading you should be able to:- Recall the symptoms, proposed aetiology and neuropathology of Parkinson’s disease Appreciate how nigrostriatal tract degeneration affects basal ganglia firing, potentially...

L17 Parkinson’s Disease and its Treatment 2 Learning Outcomes After this lecture and appropriate reading you should be able to:- Recall the symptoms, proposed aetiology and neuropathology of Parkinson’s disease Appreciate how nigrostriatal tract degeneration affects basal ganglia firing, potentially leading to the movement deficit in Parkinson’s disease Discuss the current drug treatments for Parkinson’s and the rationale behind their use Appreciate the limitations of current drug treatments 3 Parkinson’s disease Age-related neurodegenerative disorder first described in 1817 Affects 0.5% population; 2% aged over 80 years Incidence 1.5x more likely in males Motor Symptoms Resting Tremor(~5Hz): Usually first shows in one hand Postural Instability: Intrinsic muscle stiffness. Stooped posture Bradykinesia: Slowness in executing movements. Delayed start and stop. Shuffling Rigidity: Increased resistance to passive limb movement. Muscle stiffness. Flexed arms, hips and knees Non-Motor Symptoms E.g. REM sleep disorder; autonomic dysfunction; cognitive decline; pain Age = key risk factor Disease can affect anyone Oestrogen is neuroprotective so less common in females, but this effect reduces following menopause. Resistance to passive limb movements Autonomic dysfunction = bladder and bowel problems. Primarily a motor disorder. 4 Aetiology of PD – remains unclear Most cases of PD are sporadic with late onset and no known cause Many possible causes suggested Genetics ~10% familial cases (mutations in PARK1-10 genes) PARK-1 encodes for α-synuclein which is overexpressed in PD Environmental toxins some toxins e.g. 1-methyl-4phenyl-1,2,5,6,tetrahydropyridine (MPTP) can induce parkinsonism in humans. Agrochemicals e.g. Pesticides – persistent accumulation? Gut microbiome? Evidence increasing that trigger could start in GIT. α-synuclein aggregates found in GIT 2 Sporadic – no obvious cause of risk factor Park 1 mutation = point mutation in alpha synuclein, which is very overexpressed in Parkinson’s patients. Mutant = aggregates and forms lesions in brain. 90% = not genetic. MPTP = induces parkinsonism – shown when addicts accidentally injected what they thought was heroin. Organic chlorine pesticides could be a cause. Gut microbiome in people with Parkinson’s distinct from healthy individuals and can be transferred to rodents to induce Parkinson’s symptoms. 5 Key neuropathology: degeneration of nigrostriatal tract loss of pigmented cell bodies in substantia nigra pars compacta neuromelanin containing dopamine cells in mid-brain SNc Degeneration of dopaminergic neurons = key pathology. Neuromelanin cause by oxidation of dopamine 3 6 The LEWY BODY Pathological hallmark of PD – not exclusive Lewy bodies Pigmented DA neuron LBs found in many remaining DAergic neurones in SNc in PD but many other areas too Stain for many proteins including α-synuclein α-synuclein aggregation is a key contributing factor to Parkinson’s Lewy body = halo-like structures – harbour alpha synuclein aggregates and cause dysfunction and death of dopaminergic neurons. Not exclusive to Parkinson’s but found in all Parkinson’s patients 7 Reduced dopamine innervation of SNc target region, the striatum, in Parkinson’s 1960- Hornykiewicz & Ehringer - striatal DA reduced in PD striatum Symptoms only appear when striatal DA reduced by 60-80% [18F]-dopa PET scan showing reduced number of DA neuron terminals in PD patient striatum caudate putamen caudate putamen Healthy Parkinson’s Disease Parkinson’s patient. SNc = Substantia nigra pars compacta Symptoms only appear when 60-80% of dopamine is lost in the striatum. Striatum = target area of substantia nigra 4 striatum 8 Pathogenesis of SNc degeneration is multi-factorial Neuroinflammation Excitotoxicity Mitochondrial dysfunction Reduced trophic factor support Alpha synuclein aggregation Dysfunction of protein breakdown (e.g. autophagy) AlDakheel et al., Neurotherapeutics (2014). 11: 6-23 Glutamate mediated excitotoxicity Protein aggregation caused by dysfunction of protein breakdown 9 How does nigrostriatal tract degeneration lead to motor deficits ? 5 10 Components and neurotransmitters in the Basal Ganglia Motor Circuit Neurotransmitter Pathways Action on target: Excitation or Inhibition Acetylcholine Striatal interneurones Excitation (M1 receptor) Dopamine Nigrostriatal pathway Excitation (D1 receptors) Inhibition (D2 receptors) GABA (gammaamino-butyric acid) Striatal output pathways; thalamic output pathways Inhibition (GABAA or GABAB receptors) Glutamate corticostriatal pathway, thalamocortical pathway Excitation (AMPA, NMDA or Kainate receptors) Caudate + putamen = striatum Basal ganglia = subcortical neurons that are responsible for coordination of neurons Relevant = ACh acting on M1in striatal interneurons – excitatory G protein receptor Dopamine can be excitatory or inhibitory depending on which receptor it acts on. D1 = coupled to Gs, D2 = coupled to Gr and Go. 11 Changes in basal ganglia motor pathways in Parkinson’s Glu Striatum motor cortex excites D2- - indirect STN direct GABA excites or inhibits Abbreviations STN: subthalamic nucleus GPe/i: globus pallidus externus / internus SNc/r: substantia nigra pars compacta / reticulata GABA GABA Glu D1++ X (Cortical glutamate output to striatum unaffected) GPe ACh i-n thalamic relay GABA nuclei GPi/SNr SNc In health: direct and indirect pathways balanced in health In PD: direct pathway underactive; Indirect pathway overactive Thalamocortical feedback is reduced, evoking motor deficits Key Dopamine Glutamate GABA Corticostriatal pathway is glutamatergic – tonically active releasing glutamate into the striatum 6 Striatum connects directly to globus pallidus internus and indirectly through other structures. When direct pathway is active it facilitates movement, when indirect pathway is activated, it inhibits movement SNc fires to flood dopamine into striatum – prevents inhibition. Direct = d1 = activates movement, d2 inhibits indirect pathway to inhibit movement Both pathways use GABA Parkinson’s = inhibition of direct and disinhibition of indirect pathway STN also disinhibited Too little GABA, too much glutamate, increased GABAergic signalling at thalamic relay nuclei = little feedback to brain Striatum also has too much acetylcholine because interneurons have d2 receptors and loss of dopamine means the interneurons are no longer inhibited 12 Changes in basal ganglia pathways in Parkinson’s (text summary) SNc degeneration means there is a loss of dopamine innervation to the basal ganglia; glutamate innervation from the cortex is still intact Basal ganglia pathways change to reflect the loss of dopamine Direct pathway (which dopamine activates) becomes UNDERACTIVE Indirect pathway (which dopamine inhibits) becomes OVERACTIVE Downstream consequences are reduction of thalamocortical feedback so reduced movement 7 A secondary change involves increased firing of striatal cholinergic interneurones 13 Current drug treatments for Parkinson’s Anticholinergic drugs / muscarinic receptor antagonists (1st drugs available) e.g. benzhexol, benzatropine Action? Loss of DA dis-inhibits striatal cholinergic interneurones Increased acetylcholine (ACh) contributes to tremor; mechanism unclear Muscarinic antagonists are effective against resting tremor Minimal effect against bradykinesia and rigidity Side effects: central e.g. confusion, mood changes Peripheral e.g. constipation, blurred vision, dry mouth useful if sialorrhea is a problem Only symptom they are useful for is tremor Lack of ACh = associated with cognitive deficits Monooxidase B breaks down dopamine in the neuron COMT breaks down dopamine in post synaptic neuron 8 15 Levodopa or L-DOPA (L-3,4-dihydroxyphenylalanine) Natural DA precursor which, unlike DA, can cross BBB. L-DOPA dopa decarboxylase (DDC) DA BUT L-DOPA is ~90% converted by DDC in intestinal wall Ø Co-administered with peripherally-acting DDC inhibitors Ø Carbidopa ( as Sinemet) or benserazide (as Madopar) L-DOPA is ~5% metabolised by plasma Catechol O-Methyl Transferase Ø COMT inhibitor, entacapone, may be used as adjunct Ensure majority of L-DOPA enters brain unchanged Conversion by DDC inside remaining DA neurones produces DA L Dopa co-administered with dopa decarboxylase inhibitor to prevent dopamine being produced in the gut, which cannot then reach the brain. COMT may also be used to reduce wasted drug 16 Therapeutic effects of L-DOPA L-DOPA with carbidopa / benserazide raises striatal DA levels Activity normalised in direct (D1) and indirect (D2) pathways Improves rigidity, bradykinesia, facial expression, speech & handwriting in ~80% people 9 17 Acute side-effects of L-DOPA Peripheral: Nausea due to remaining peripheral DA-R activation - Peripheral DA receptor antagonist, domperidone, given as adjunct Postural hypotension (esp. in patients on anti-hypertensive drugs) Central: hallucinations, confusion, insomnia or nightmares Too much dopamine in gut = nausea 18 Side-effects of chronic L-DOPA Within 5 years of starting L-DOPA therapy around 1/3 patients develop: 1) Motor fluctuations (‘on-off’ effect) Rapid fluctuations in clinical state. Freezing may last min or hours. 2) Levodopa-induced dyskinesia (LID) Excess, hyperkinetic involuntary movements (choreic or dystonic). - Face, limbs and trunk mostly affected. Patients go from being underactive to overactive 10 19 L-DOPA-induced dyskinesia 20 Side-effects of chronic L-DOPA Within 5 years of starting L-DOPA therapy around 1/3 patients develop: 1)motor fluctuations (‘on-off’ effect) Rapid fluctuations in clinical state. Freezing may last min or hours. 2) Levodopa-induced dyskinesia (LID) Excess, hyperkinetic involuntary movements (choreic or dystonic). - Face, limbs and trunk mostly affected. - Seem to be related to fluctuations in levels of dopamine activating receptors -Thalamocortical feedback is increased with additional evidence of abnormally increased glutamatergic corticostriatal transmission Amantadine (NMDA-type glutamate receptor antagonist only drug offering some relief Aim to delay introduction of L-DOPA for as long as possible in most patients Delay L-DOPA introduction as long as possible. 11 21 Monoamine Oxidase-B Inhibitors e.g. selegiline or rasagiline Monoamine oxidase B (MAO-B) is principal route of dopamine (DA) metabolism MAO-B Dopamine X DOPAC (dihydroxyphenylacetic acid) MAO-B inhibitors block DA metabolism thereby prolonging DA activity May be used as monotherapy in early stage PD to boost remaining DA activity Often used as an adjunct to lower L-DOPA dose in later disease (L-DOPA sparing) Endogenous dopamine can act for longer or can be given alongside LDOPA to increase its duration of action and reduce needed L-DOPA dose which can reduce the risk of L-DOPA induced dyskinesias “L-DOPA sparing strategies” 22 Dopamine receptor agonists e.g. bromocriptine, ropinirole, pramipexole Produce effects mainly through activation of striatal D2 receptors Acute side effects – as for L-DOPA Chronic side effects: less incidence of dyskinesia Ø Longer acting (>t1/2) than L-DOPA so maybe less fluctuation in receptor stimulation Used first or after MAO-B inhibitors stop being effective. BUT less effective than L-DOPA in relieving symptoms, so L-DOPA needed eventually Used as adjuncts to lower L-DOPA dose when L-DOPA required Correct overactivity of inhibitory pathway Longer acting drugs than L-DOPA 12 23 Alternative routes of drug administration to reduce dyskinesia Rotigotine (dopamine agonist) patch: Effective as monotherapy in early PD Duo-dopa: intraduodenal pump to Produodopa (fos-levodopa + foscarbidopa): continuous s.c. delivery provide L-DOPA infusion to provide less fluctuation in receptor activation via pump. Approved Oct 2023 24 Failings of Current Treatments Only treat some of the symptoms Postural imbalance left unaffected Side effects Very disabling in some cases ; dyskinesia Do not address the progressive degeneration - Urgent need for neuroprotective or repair treatments Need to address fall risk particularly in elderly patients All symptomatic drugs 13 25 Suggested References Crossman AR (2000). Functional anatomy of movement disorders. J. Anatomy 196: 519-525 General pharmacology text books for treatment e.g. Rang and Dale’s Pharmacology (8th Edition); Chapter 40: p491-496 Kakkar & Dahiya (2015). Management of Parkinson‫׳‬s disease: Current and future pharmacotherapy. Eur J Pharmacol 750:74-81 14