(1) Amphetamine in neuroregeneration: AM post-treatment significantly reduced neurological deficits, as measured by body asymmetry and Bedersons score in stroke rats. T2WI and diffusion tensor imaging (DTI) were used to examine the size of infarction and axonal reinnervation, respectively, before and following treatment on days 2, 10 and 25 after stroke. AM treatment reduced the volume of tissue loss on days 10 and 25. A significant increase in fractional anisotropy ratio was found in the ipislateral cortex after repeated AM administration, suggesting a possible increase in axonal outgrowth in the lesioned side cortex. Western analysis indicated that AM significantly increased the expression of synaptophysin ipsilaterally and neurofilament bilaterally. AM also enhanced matrix metalloproteinase (MMP) enzymatic activity, determined by MMP zymography in the lesioned side cortex. qRT-PCR was used to examine the expression of trophic factors after the 1st and 2nd doses of AM or saline injection. The expression of BDNF, but not BMP7 or CART, was significantly enhanced by AM in the lesioned side cortex. In conclusion, post-stroke treatment with AM facilitates behavioral recovery, which is associated with an increase in fractional anisotropy activity, enhanced fiber growth in tractography, synaptogenesis, upregulation of BDNF, and MMP activity mainly in the lesioned cortex. Our data suggest that the ipsilateral cortex may be the major target of action in stroke brain after AM treatment. (2) adenosine A3R receptor: We reported that high doses of Meth suppressed locomotor activity in adult male A3R null mutant (-/-) mice and their controls (+/+), with a greater reduction being found in the -/- mice. Brain tissues were collected at 3 days after the Meth or saline injections. Meth treatment reduced striatal dopamine (DA) levels in both +/+ and -/- mice, examined by HPLC, with an increase in DOPAC/DA ratio being found only in -/- animals after Meth treatment. Meth also significantly increased ionized calcium-binding adaptor molecule 1 (Iba-1) and cleaved caspase-3 level in striatum as well as Iba-1 and TNF mRNA expression in nigra in -/-, compared to +/+, mice. Previous studies have shown that pharmacological suppression of VMAT2 by reserpine enhanced Meth toxicity by increasing cytosolic DA and inflammation. A significant reduction in striatal VMAT2 expression was found in -/- mice, compared to +/+ mice, suggesting that increase in sensitivity to Meth injury in -/- mice may be related to a reduction in VMAT2 expression in these mice. Our data suggest that A3R -/- mice are more sensitive to high doses of Meth. (3) pifithrin-a (PFT-a): (A) We found that PFTa has protective against Meth -mediated injury in dopaminergic neurons. High dose of Meth reduced TH immunoreactivity and fiber density in primary dopaminergic neuronal culture. Co-treatment with PFTa significantly attenuated these degenerative changes. Our data suggest that treatment with a p53 inhibitor or suppression of p53 expression limits neuronal dysfunction and cell death induced by exposure to dopaminergic neurotoxins. (B) Systemic administration of PFT- enhanced the survival of dopaminergic neuronal transplants in vivo. PFT- treatment suppressed cell death, increased survival of TH (+) cells, enhanced TH neurite outgrowth from ventromesencephalic grafts, and augmented behavioral recovery in Parkinsonian rats. In conclusion, our data suggest that activation of p53 is an important mediator for cell death after injury or during neural repair. Transient suppression of p53 may increase the survival of neurons or NPCs after brain injury. (4) Retinoic acid (RA): Pretreatment with 9 cis RA (9cRA) increased locomotor activity, attenuated neurological deficits, and reduced cerebral infarction and TUNEL labeling in stroke rats. 9cRA increased the expression of bone morphogenetic protein 7 (BMP7) in brain. The protective response of 9cRA can be antagonized by BMP antagonist noggin. Our data suggest that RA can induce protective responses against Meth toxicity in cultured cells and in vivo, possibly through BMP7 mechanism. (5) (-)Naloxone: Neurodegeneration can occur through the activation of inflammatory processes. From experiments conducted this past year, we have observed improved behavioral recovery (body asymmetery and neurological score) following stroke when (+)naloxone was administered daily for 1 week starting one day after middle cerebral artery occlusion in rats. We are currently following up these studies comparing (-)naloxone as well as examining changes in markers of inflammation that are upregulated following ischemia of the stroke.

Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2013
Total Cost
$270,376
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
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He, Yi; Yu, Seongjin; Bae, Eunkyung et al. (2013) Methamphetamine alters reference gene expression in nigra and striatum of adult rat brain. Neurotoxicology 39C:138-145
Luo, Yu; Shen, Hui; Liu, Hua-Shan et al. (2013) CART peptide induces neuroregeneration in stroke rats. J Cereb Blood Flow Metab 33:300-10
Henderson, Mark J; Richie, Christopher T; Airavaara, Mikko et al. (2013) Mesencephalic astrocyte-derived neurotrophic factor (MANF) secretion and cell surface binding are modulated by KDEL receptors. J Biol Chem 288:4209-25
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Yu, Seong-Jin; Airavaara, Mikko; Shen, Hui et al. (2012) Suppression of endogenous PPARγ increases vulnerability to methamphetamine-induced injury in mouse nigrostriatal dopaminergic pathway. Psychopharmacology (Berl) 221:479-92
Harvey, Brandon K; Airavaara, Mikko; Hinzman, Jason et al. (2011) Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke. PLoS One 6:e22135
Shen, Hui; Harvey, Brandon K; Chiang, Yung-Hsiao et al. (2011) Methamphetamine potentiates behavioral and electrochemical responses after mild traumatic brain injury in mice. Brain Res 1368:248-53
Airavaara, Mikko; Voutilainen, Merja H; Wang, Yun et al. (2011) WITHDRAWN: Neurorestoration. Parkinsonism Relat Disord :
Cadet, Jean Lud; Brannock, Christie; Krasnova, Irina N et al. (2010) Methamphetamine-induced dopamine-independent alterations in striatal gene expression in the 6-hydroxydopamine hemiparkinsonian rats. PLoS One 5:e15643
Luo, Yu; Wang, Yun; Kuang, Serena Y et al. (2010) Decreased level of Nurr1 in heterozygous young adult mice leads to exacerbated acute and long-term toxicity after repeated methamphetamine exposure. PLoS One 5:e15193

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