Parkinson's disease pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
The underlying [[pathophysiology]] of [[Parkinson's disease|Parkinson disease]] is [[dopamine]] depletion.The [[substantia nigra]] ([[Substantia nigra|SN]]), [[striatum]] ([[Caudate nucleus|caudate]] and [[putamen]]), [[globus pallidus]] ([[Globus pallidus|GP]]), [[subthalamic nucleus]] ([[Subthalamic nucleus|STN]]) and [[thalamus]] contribute with each other to make the [[extrapyramidal system]] or [[basal ganglia]]. The impulses from [[hippocampus]], [[amygdala]] and prefrontal supplementary motor area to the [[basal ganglia]] are [[Excitatory synapse|excitatory]] mediated by [[glutamate]]. The major [[dopaminergic]] [[neurons]] are in [[substantia nigra]] and are responsible for [[dopaminergic]] input of [[striatum]]. The striatal output is [[Inhibitory synapses|inhibitory]] ([[GABA]]) despite the [[Excitatory synapse|excitatory]] ([[glutamate]]) output of [[Subthalamic nucleus|STN]] to the [[globus pallidus]] (medial and lateral). There are 5 [[dopamine receptors]] (D1_D5) which are in [[basal ganglia]] and [[limbic system]]. [[D1 receptor|D1]] and [[D2 receptor|D2]] are mostly found in the dorsal [[striatum]] (motor) and are activated through [[dopaminergic]] pathway from [[Substantia nigra|SNc]], as a result, they are very important in the [[pathophysiology]] of Parkinson disease. D3 and D4 are located mostly in [[Mesolimbic system|mesolimbic]] or emotional part of the [[brain]] and D5 in [[hippocampus]]/[[hypothalamus]] area.<ref name="pmid11052222">{{cite journal |vauthors=Gerfen CR |title=Molecular effects of dopamine on striatal-projection pathways |journal=Trends Neurosci. |volume=23 |issue=10 Suppl |pages=S64–70 |date=October 2000 |pmid=11052222 |doi= |url=}}</ref> In the course of the disease [[dopamine]] depletion of [[nigrostriatal pathway]] will lead to denervation hypersensitivity and increasing number of [[D2 receptor|D2]] receptors in dorsal [[putamen]].<ref name="pmid15509741">{{cite journal |vauthors=Bamford NS, Robinson S, Palmiter RD, Joyce JA, Moore C, Meshul CK |title=Dopamine modulates release from corticostriatal terminals |journal=J. Neurosci. |volume=24 |issue=43 |pages=9541–52 |date=October 2004 |pmid=15509741 |doi=10.1523/JNEUROSCI.2891-04.2004 |url=}}</ref> There are two pathways in this system: Direct and indirect pathway. In the indirect pathway starts with [[inhibition]] of [[striatum]] via [[D2 receptor]] which in turn [[Inhibition|inhibits]] [[neurons]] of lateral [[Globus pallidus|GP]] by [[GABA]] which [[Inhibition|inhibits]] the inhibition of [[Subthalamic nucleus|STN]] by lateral [[Globus pallidus|GP]]. [[Subthalamic nucleus|STN]] provides [[Excitatory synapse|excitatory]] action on [[Globus pallidus|GP]] internal and [[Substantia nigra|SNr]] via [[glutamate]]. [[Globus pallidus|GPi]] inhibit [[thalamus]] by [[GABA]] but [[cortex]] input from [[thalamus]] is [[Excitatory synapse|excitatory]]. Direct pathway starts with [[excitation]] of [[striatum]] by stimulation of [[D1 receptor|D1 receptors]], then [[striatum]] inhibits [[Globus pallidus|GP]] internal and [[Substantia nigra|SNr]] by [[GABA]] directly. Reduced number of [[dopaminergic]] [[neurons]] lead to increased inhibition of [[thalamus]] and as a result, decrease excitation of [[Cortex|brain cortex]], causing [[bradykinesia]].<ref name="pmid16830313">{{cite journal |vauthors=Gatev P, Darbin O, Wichmann T |title=Oscillations in the basal ganglia under normal conditions and in movement disorders |journal=Mov. Disord. |volume=21 |issue=10 |pages=1566–77 |date=October 2006 |pmid=16830313 |doi=10.1002/mds.21033 |url=}}</ref> | The underlying [[pathophysiology]] of [[Parkinson's disease|Parkinson disease]] is [[dopamine]] depletion.The [[substantia nigra]] ([[Substantia nigra|SN]]), [[striatum]] ([[Caudate nucleus|caudate]] and [[putamen]]), [[globus pallidus]] ([[Globus pallidus|GP]]), [[subthalamic nucleus]] ([[Subthalamic nucleus|STN]]) and [[thalamus]] contribute with each other to make the [[extrapyramidal system]] or [[basal ganglia]]. The impulses from [[hippocampus]], [[amygdala]] and prefrontal supplementary motor area to the [[basal ganglia]] are [[Excitatory synapse|excitatory]] mediated by [[glutamate]]. The major [[dopaminergic]] [[neurons]] are in [[substantia nigra]] and are responsible for [[dopaminergic]] input of [[striatum]]. The striatal output is [[Inhibitory synapses|inhibitory]] ([[GABA]]) despite the [[Excitatory synapse|excitatory]] ([[glutamate]]) output of [[Subthalamic nucleus|STN]] to the [[globus pallidus]] (medial and lateral). There are 5 [[dopamine receptors]] (D1_D5) which are in [[basal ganglia]] and [[limbic system]]. [[D1 receptor|D1]] and [[D2 receptor|D2]] are mostly found in the dorsal [[striatum]] (motor) and are activated through [[dopaminergic]] pathway from [[Substantia nigra|SNc]], as a result, they are very important in the [[pathophysiology]] of Parkinson disease. D3 and D4 are located mostly in [[Mesolimbic system|mesolimbic]] or emotional part of the [[brain]] and D5 in [[hippocampus]]/[[hypothalamus]] area.<ref name="pmid11052222">{{cite journal |vauthors=Gerfen CR |title=Molecular effects of dopamine on striatal-projection pathways |journal=Trends Neurosci. |volume=23 |issue=10 Suppl |pages=S64–70 |date=October 2000 |pmid=11052222 |doi= |url=}}</ref> In the course of the disease [[dopamine]] depletion of [[nigrostriatal pathway]] will lead to denervation hypersensitivity and increasing number of [[D2 receptor|D2]] receptors in dorsal [[putamen]].<ref name="pmid15509741">{{cite journal |vauthors=Bamford NS, Robinson S, Palmiter RD, Joyce JA, Moore C, Meshul CK |title=Dopamine modulates release from corticostriatal terminals |journal=J. Neurosci. |volume=24 |issue=43 |pages=9541–52 |date=October 2004 |pmid=15509741 |doi=10.1523/JNEUROSCI.2891-04.2004 |url=}}</ref> There are two pathways in this system: Direct and indirect pathway. In the indirect pathway starts with [[inhibition]] of [[striatum]] via [[D2 receptor]] which in turn [[Inhibition|inhibits]] [[neurons]] of lateral [[Globus pallidus|GP]] by [[GABA]] which [[Inhibition|inhibits]] the inhibition of [[Subthalamic nucleus|STN]] by lateral [[Globus pallidus|GP]]. [[Subthalamic nucleus|STN]] provides [[Excitatory synapse|excitatory]] action on [[Globus pallidus|GP]] internal and [[Substantia nigra|SNr]] via [[glutamate]]. [[Globus pallidus|GPi]] inhibit [[thalamus]] by [[GABA]] but [[cortex]] input from [[thalamus]] is [[Excitatory synapse|excitatory]]. Direct pathway starts with [[excitation]] of [[striatum]] by stimulation of [[D1 receptor|D1 receptors]], then [[striatum]] inhibits [[Globus pallidus|GP]] internal and [[Substantia nigra|SNr]] by [[GABA]] directly. Reduced number of [[dopaminergic]] [[neurons]] lead to increased inhibition of [[thalamus]] and as a result, decrease excitation of [[Cortex|brain cortex]], causing [[bradykinesia]].<ref name="pmid16830313">{{cite journal |vauthors=Gatev P, Darbin O, Wichmann T |title=Oscillations in the basal ganglia under normal conditions and in movement disorders |journal=Mov. Disord. |volume=21 |issue=10 |pages=1566–77 |date=October 2006 |pmid=16830313 |doi=10.1002/mds.21033 |url=}}</ref> Our [[brain]] has some compensatory mechanism fighting [[dopamine]] depletion. It can increase the synthesis of [[dopamine]], [[gap junctions]] and the number of [[D2 receptor|D2 receptors]]. It can also reduce the uptake of dopamine from synaptic space.(10-11-15) | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
The underlying pathophysiology of Parkinson disease is dopamine depletion.The substantia nigra (SN), striatum (caudate and putamen), globus pallidus (GP), subthalamic nucleus (STN) and thalamus contribute with each other to make the extrapyramidal system or basal ganglia. The impulses from hippocampus, amygdala and prefrontal supplementary motor area to the basal ganglia are excitatory mediated by glutamate. The major dopaminergic neurons are in substantia nigra and are responsible for dopaminergic input of striatum. The striatal output is inhibitory (GABA) despite the excitatory (glutamate) output of STN to the globus pallidus (medial and lateral). There are 5 dopamine receptors (D1_D5) which are in basal ganglia and limbic system. D1 and D2 are mostly found in the dorsal striatum (motor) and are activated through dopaminergic pathway from SNc, as a result, they are very important in the pathophysiology of Parkinson disease. D3 and D4 are located mostly in mesolimbic or emotional part of the brain and D5 in hippocampus/hypothalamus area.[1] In the course of the disease dopamine depletion of nigrostriatal pathway will lead to denervation hypersensitivity and increasing number of D2 receptors in dorsal putamen.[2] There are two pathways in this system: Direct and indirect pathway. In the indirect pathway starts with inhibition of striatum via D2 receptor which in turn inhibits neurons of lateral GP by GABA which inhibits the inhibition of STN by lateral GP. STN provides excitatory action on GP internal and SNr via glutamate. GPi inhibit thalamus by GABA but cortex input from thalamus is excitatory. Direct pathway starts with excitation of striatum by stimulation of D1 receptors, then striatum inhibits GP internal and SNr by GABA directly. Reduced number of dopaminergic neurons lead to increased inhibition of thalamus and as a result, decrease excitation of brain cortex, causing bradykinesia.[3] Our brain has some compensatory mechanism fighting dopamine depletion. It can increase the synthesis of dopamine, gap junctions and the number of D2 receptors. It can also reduce the uptake of dopamine from synaptic space.(10-11-15)
References
- ↑ Gerfen CR (October 2000). "Molecular effects of dopamine on striatal-projection pathways". Trends Neurosci. 23 (10 Suppl): S64–70. PMID 11052222.
- ↑ Bamford NS, Robinson S, Palmiter RD, Joyce JA, Moore C, Meshul CK (October 2004). "Dopamine modulates release from corticostriatal terminals". J. Neurosci. 24 (43): 9541–52. doi:10.1523/JNEUROSCI.2891-04.2004. PMID 15509741.
- ↑ Gatev P, Darbin O, Wichmann T (October 2006). "Oscillations in the basal ganglia under normal conditions and in movement disorders". Mov. Disord. 21 (10): 1566–77. doi:10.1002/mds.21033. PMID 16830313.