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Dopamine and cAMP Regulated Phosphoprotein, 32 kDA: A Novel Therapeutic in Traumatic Brain Injury

Bales, James William (2010) Dopamine and cAMP Regulated Phosphoprotein, 32 kDA: A Novel Therapeutic in Traumatic Brain Injury. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Traumatic brain injury (TBI) represents a significant cause of death and disability in industrialized countries. Of particular importance to patients is the chronic effect that TBI has on cognitive function. Therapeutic strategies have been difficult to evaluate because of the complexity of injuries and variety of patient presentations within a TBI population. Experimental therapies based upon cortical and hippocampal neuroprotection have not translated clinically. However, pharmacotherapies targeting dopamine (DA) have consistently shown benefits in attention, behavioral outcome, executive function, and memory. Striatal damage causes deficits in executive function, learning, and memory. Dopamine and cAMP regulated phosphoprotein 32 (DARPP-32), expressed within striatal medium spiny neurons, is known to regulate several substrates of cognition. We found that controlled cortical impact injury in rats produces a chronic decrease in DARPP-32 threonine-34 phosphorylation and increase in protein phosphatase-1 activity. There is no effect of injury on threonine-75 phosphorylation or DARPP-32 protein. Amantadine has known benefits on post-TBI cognitive deficits and when given daily for two weeks reversed the DARPP-32 and protein phosphatase-1 changes. Amantadine also decreased the phosphorylation of threonine-75 consistent with activity as a partial N-methyl-D-aspartic acid receptor antagonist and partial dopamine agonist. FK-506, also known as tacrolimus, is a calcineurin inhibitor that has been shown to decrease cell death in the hippocampus following a fluid percussion experimental TBI. Calcineurin is also an important regulator of DARPP-32 phosphorylation in the striatum. We evaluated the effect of FK-506 on the hippocampus and DARPP-32 in the striatum to better detail its effects after a TBI. An acute administration of FK-506 following controlled cortical impact reversed the effects of TBI on DARPP-32 phosphorylation seen chronically. We then evaluated the effect of a combined drug therapy on cognitive deficits post TBI. An acute treatment with FK-506 post TBI followed by chronic Amantadine therapy demonstrated an improvement in both motor behavior and Morris water maze deficits seen following TBI. Neither drug produced benefit when given alone. These data demonstrate that DARPP-32 represents a promising new therapeutic target for TBI induced cognitive deficits.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Bales, James
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGraham, Stevengrahams@upmc.eduSGRA
Committee MemberWagner, Amywagnerak@upmc.eduAKW4
Committee MemberKline, Anthony Eklineae@upmc.eduAEKLINE
Committee MemberGrace, Anthonygraceaa@pitt.eduGRACEAA
Committee MemberDixon, C.
Committee MemberReeves,
Date: 26 July 2010
Date Type: Completion
Defense Date: 12 July 2010
Approval Date: 26 July 2010
Submission Date: 15 July 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: amantadine; calcineurin; DARPP-32; dopamine; fk-506; pharmacotherapy; striatum; traumatic brain injury
Other ID:, etd-07152010-093018
Date Deposited: 10 Nov 2011 19:51
Last Modified: 19 Dec 2016 14:36


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