The focus of my research is to understand the molecular signaling and effector pathways involved in microglial activation, and the impact of these on neurodegeneration and neurogenesis. This work has recently focused on poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a nuclear enzyme that is involved in single strand DNA repair. When activated, PARP-1 consumes NAD in order to produce ADP-riboses and over- /hyper-activation of PARP-1 leads to energy depletion. Thus in pathologies including robust DNA damage (e.g. ischemic stroke) inhibition of PARP-1 has been shown to improve neuronal survival. PARP-1 also functions as a co-activator of transcription factors, such as NF-kB. This function of PARP-1 has been considered to be responsible for PARP-1's ability to regulate inflammatory responses, including microglial activation. Microglial activation and inflammatory responses in general can enhance neurodegeneration and reduce neurogenesis (attenuate survival of progenitor cells or even reduce progenitor cell proliferation).

I see PARP-1 is as a critical integrating factor in neurodegeneration, neuroinflammation and neurogenesis, and thus potential target for therapeutic approaches. It is important to aim towards better understanding of PARP-1's role and regulation.

Ongoing projects:

1. Effects of energy supplementation on PARP-1-mediated cell death
2. Neurogenesis and microglial activation
3. PARP-1 mediated regulation of microglial function
4. The molecular pathways leading to PARP-1 activation after inflammatory stimuli
5. The gross-regulation between PARP-1 and MAPK
6. MinocyclineÕs effect on PARP-1 activation
7. The role of PARG in PARP-1 regulation

1. Vartiainen N, Tikka T, Keinanen R, Chan PH, Koistinaho J. Glutamatergic receptors regulate expression, phosphorylation and accumulation of neurofilaments in spinal cord neurons. Neuroscience. 1999;93(3):1123-33.

2. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496-500.

3. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001 Apr 15;21(8):2580-8.

4. Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001 Jun 15;166(12):7527-33.

5. Tikka T, Usenius T, Tenhunen M, Keinanen R, Koistinaho J. Tetracycline derivatives and ceftriaxone, a cephalosporin antibiotic, protect neurons against apoptosis induced by ionizing radiation. J Neurochem. 2001 Sep;78(6):1409-14.

6. Tikka TM, Vartiainen NE, Goldsteins G, Oja SS, Andersen PM, Marklund SL, Koistinaho J. Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brain. 2002 Apr;125(Pt 4):722-31.

7. Sevigny M, Garnier P, Kauppinen T, Swanson R. Heat shock - induced Hsp70 expression in murine astrocytes does not require poly(ADP-ribose) polymerase activity. Cell Physiol Biochem. 2003;13(5):297-300.

8. Koistinaho J, Yrjanheikki J, Kauppinen T, Koistinaho M. Tetracycline derivatives as anti-inflammatory agents and potential agents in stroke treatment. Ernst Schering Res Found Workshop. 2004;(47):101-15. Review.

9. Swanson RA, Ying W, Kauppinen TM. Astrocyte influences on ischemic neuronal death. Curr Mol Med. 2004 Mar;4(2):193-205. Review.

10. Kauppinen TM, Swanson RA. Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death. J Immunol. 2005 Feb 15;174(4):2288-96.

11. Kauppinen TM, Suh SW, Genain CP, Swanson RA. Poly(ADP-ribose) polymerase-1 activation in a primate model of multiple sclerosis. J Neurosci Res. 2005 Jul 15;81(2):190-8.

12. Kauppinen TM, Chan WY, Suh SW, Wiggins AK, Huang EJ, Swanson RA. Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2. Proc Natl Acad Sci U S A. 2006 May 2;103(18):7136-41.

13. Alano CC, Kauppinen TM, Valls AV, Swanson RA. Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9685-90.

14. Kauppinen TM, Swanson RA. The role of Glia in Excitotoxicity and Stroke. In: Chan PH (eds) Handbook of Neurochemistry, 3^rd Edition. In press.

15. Kauppinen TM, Swanson RA. The role of poly(ADP-ribose)polymerase-1 in CNS disease. Neuroscience. Review. In press.