Faculty Information

Kai U. Frerichs, M.D.

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Narrative Report

In 1986, I developed and published the first reliable disease model for cerebral sinus and venous thrombosis in rats. This model has subsequently been used by me and other laboratories to investigate the pathophysiology of this disease as well as effective treatments based on improved understanding of the underlying mechanisms of damage. The goal of my subsequent research has been to develop novel neuroprotective strategies for stroke and neurotrauma. In 1990, I established a new model for traumatic brain injury in rodents using a Nd:YAG laser source. This model has the advantage of being highly reproducible overcoming one of the most serious shortcomings of conventional models. With the help of this model platelet activating factor (PAF) was identified as a major mediator in the development of neuronal damage and PAF antagonists are being evaluated in clinical trials. Recently, we introduced a new conceptual approach to the development of neuroprotective strategies. This effort was triggered by the persistent failure of more conventional approaches to develop effective neuroprotective agents. Conventional neuroprotection research is generally based on the assumption that a single mediator accounts for the majority of damage following stroke or trauma. There is a finite possibility that this assumption is wrong. Instead, a multitude of mediators and pathologic events may act in concert in a network of "minor causes" without clear sequence and directionality. As an alternative to the analysis of such individual mediators following pathologic events, we proposed to investigate states of tolerance, natural and induced, in which damage does not occur. Such investigations may lead to novel neuroprotective strategies. We have studied and identified mammalian hibernation as a such a state of tolerance. We could show that the resistance to neurological damage in this natural model is independent of temperature and is even preserved in vitro in hippocampal slices. Furthermore, we have identified several processes that appear critical in the regulation of this tightly controlled state. These include a virtual arrest of global protein synthesis sustained for up to weeks at a time. Identification of the preceding mechanisms of the global cellular arrest should lead to the triggers and signals of the state of tolerance. Such signals may be applicable to induce tolerance in other species including humans.

Funding Information

This research was supported by the Intramural Program of the National Institutes of Health.

Report of Current Research Activities

1. Mechanisms of neuroprotection in nature
2. Rapid therapeutic induction of hypothermia by sulfur hexafluoride inhalation in head injured patients
3. Outcome of patients with AVMs treated by microsurgery versus radiosurgery

Report of teaching: Local contributions

Regional, National and International Contributions: Invited Lectures

Original Articles

1. FRERICHS KU, Deckert M, Jansen M, Kempski O, Einhäupl K, Baethmann A: Brain Function and Morphology in Experimental Sinus-Vein Thrombosis. J CEREB BLOOD FLOW METAB, 7:57, 1987
2. FRERICHS KU, Lindsberg PJ, Hallenbeck JM, Feuerstein GZ: Long-Term Sampling of Cerebral Venous Blood in Conscious Rats. J CEREB BLOOD FLOW METAB 1989, 9:902-905
3. FRERICHS KU, Lindsberg PJ, Hallenbeck JM, Feuerstein GZ: Platelet-Activating Factor and Progressive Brain Damage Following Focal Brain Injury. J NEUROSURG 1990, 73:223-233
4. FRERICHS KU, Lindsberg PJ, Hallenbeck JM, Feuerstein GZ: Increased Cerebral Lactate Output to Cerebral Venous Blood after Forebrain Ischemia. STROKE 1990, 21(4):614-617
5. Lindsberg PJ, Yue T-L, FRERICHS KU, Hallenbeck JM, Feuerstein G: Evidence for Platelet-Activating Factor as a Novel Mediator in Stroke in Rabbits. STROKE 1990, 21:1452-1457
6. Lindsberg PJ, FRERICHS KU, Hallenbeck JM, Feuerstein G: Cortical Microcirculation in a New Model of Focal Laser-Induced Secondary Brain Damage. J CEREB BLOOD FLOW METAB 1991, 11:88-98
7. FRERICHS KU, Sirén Al, Feuerstein GZ, Hallenbeck JM: The Onset of Postischemic Hypoperfusion in Rats is Precipitous and may be Controlled by Local Neurons. STROKE 1992, 23:399-406
8. Lindsberg PJ, Jacobs TP, FRERICHS KU, Hallenbeck JM, Feuerstein GZ: Laser-Doppler flowmetry in monitoring regulation of rapid microcirculatory changes in spinal cord. AM J PHYSIOL 1992, 263:H285-H292
9. Hallenbeck JM, FRERICHS KU: Stroke Therapy. It may be Time for an Integrated Approach. ARCH NEUROL 1993, 50:768-770
10. Xu K, Naveri L, FRERICHS KU, Hallenbeck JM, Feuerstein GZ, Davis JN, Siren AL: Extracellular Catecholamine Levels in Rat Hippocampus after a Selective Alpha-2 Adrenoceptor Antagonist or a Selective Dopamine Uptake Inhibitor: Evidence for Dopamine Release from Local Dopaminergic Nerve Terminals. J PHARMACOL EXP THER 1993, 267:211-7
11. FRERICHS KU, Kenndey C, Sokoloff L, Hallenbeck JM: Local Cerebral Blood Flow During Hibernation, a Model of Natural Tolerance to Cerebral Ischemia, J CEREB BLOOD FLOW METAB 1994, 14:193-205
12. FRERICHS KU, Deckert M, Kempski O, Schürer L, Einhäupl E, Baethmann A: Cerebral Sinus and Venous Thrombosis in Rats Induces Long-Term Deficits in Brain Function and Morphology - Evidence for a Cytotoxic Genesis. J CEREB BLOOD FLOW METAB 1994, 14:289-300
13. FRERICHS KU, DIENEL GA, CRUZ NF, SOKOLOFF L, HALLENBECK JM: Rates of glucose utilization in brain of active and hibernating ground squirrels, AM J PHYSIOL 1995, 268:R445-R453
14. Lindsberg PJ, FRERICHS KU, Siren AL, Hallenbeck JM, Nowak TS: Heat-shock protein and c-fos expression in focal microvascular brain damage, J CEREB BLOOD FLOW METAB 1996, 16:82-91
15. Lindsberg PJ, FRERICHS KU, Siren AL, Hallenbeck JM, Nowak TS: Heat-Shock Protein and C-fos Expression in Focal Microvascular Brain Damage. J CEREB BLOOD FLOW METAB 1996, 16:82-91
16. Polychronidis JE, Dutka AJ, Mink RB, FRERICHS KU: Effects of the Trendelenburg Position on Intracranial Pressure and Blood-Brain Barrier after Canine Cerebral Air Embolism UNDERSEA BIOMED RES (in press)
17. Ohtsuki T, Jaffe H, Brenner M, Azzam N, Azzam R, FRERICHS KU, Hallenbeck JM: Stimulation of Tyrosine Phosphorylation of a Brain Protein by Hibernation. J CEREB BLOOD FLOW METAB 1998, 18:1040-1045
18. FRERICHS KU, Hallenbeck JM: Hibernation in ground squirrels induces state and species-specific tolerance to hypoxia and aglycemia: an in vitro study in hippocampal slices. J CEREB BLOOD FLOW METAB 1998 18:168-75
19. FRERICHS KU, Smith CB, Brenner M, DeGracia DJ, Krause GS, Marrone L, Dever TE, Hallenbeck JM: Suppression of Protein Synthesis in Brain during Hibernation Involves Inhibition of Protein Initiation and Elongation . Proc Natl Acad Sci USA 1998, 95:14511-14516
20. FRERICHS KU: Tolerance to Cerebral Ischemia During Mammalian Hibernation. ACTA NEUROCHIRUGICA 1999, 73:57-61
21. Drew KL, Osborne PG, FRERICHS KU, Hu Y, Koren RE, Rice M: Ascorbate Regulation in Hibernating Ground Squirrels Suggests a Role for Antioxidants in Natural Tolerance to Cerebral Ischemia. Stroke 2000 (in press)

Proceedings of Meetings

1. Jansen M, Deckert M, FRERICHS KU, Einhäupl K, Baethmann A: A New Experimental Model of Sinus Thrombosis in Rats. In ADVANCES IN NEUROSURGERY. Wüllenweber M, Klinger E, Brock M, (eds.), Springer, New York, Vol.15, pp. 63-66, 1987
2. Lindsberg PJ, FRERICHS KU, Burris JA, Feuerstein G: The Effect of Nd:YAG Laser on Rat Brain Morphology and Microcirculation. LAS SURG MED Suppl 1:6, 1989
3. FRERICHS KU, Deckert M, Kempski O, Einhäupl K, Baethmann A: Brain Function, Pathophysiology and Heparin Therapy in Experimental Cerebral Sinus Vein Thrombosis. In CEREBRAL SINUS THROMBOSIS: EXPERIMENTAL AND CLINICAL ASPECTS. Einhäupl K, Kempski O, Baethmann A (eds.), PP 53-58, 1990
4. Deckert M, FRERICHS K, Mehrain P, Kempski O, Baethmann A, Einhäupl K: A New Experimental Model of Sinus Vein Thrombosis. In CEREBRAL SINUS THROMBOSIS: EXPERIMENTAL AND CLINICAL ASPECTS. Einhäupl K, Kempski O, Baethmann A (eds.), PP 39-42, 1990
5. Rüther A, FRERICHS KU, Schürer L, Kempski O, Baethmann A: Electrical Impedance, ICP and Histology in Rats with Sagittal Sinus Occlusion. In Intracranial Pressure VIII Avezaat CJJ, Eijndhoven AIR, Tans JThJ (eds.), PP 166-169, 1993

Books, Monographs, and Text Books

1. FRERICHS KU: Tolerance to Cerebral Ischemia During Mammalian Hibernation. ACTA NEUROCHIRUGICA 1999, 73:57-61

Thesis

1. Ph.D. Thesis, Institute for Surgical Research,Klinikum Grosshadern, Ludwig-Maximilians-University, Munich University:
2. "The Pathophysiology of Cerebral Sinus and Venous Thrombosis" (Summa Cum Laude)

Scientific Videotape

1. Schürer L, FRERICHS KU, Deckert M, Prügner U, Rüther A, Einhäupl K, Kempski O, Baethmann A: A New Experimental Model of Sinus-Vein Thrombosis in the Rat. 2nd Congress of the European Association of Video-Surgery. Turin, Italy, Sept. 6-8, 1990

Abstracts

1. FRERICHS KU, Hallenbeck JM, Feuerstein GZ, Sirén A-L: Release of Platelet-Activating Factor in the Penumbral Area of Focal Brain Injury. SOCIETY FOR NEUROSCIENCE, Abstracts Vol. 16, Part 2:1278, 1990
2. Xu K, FRERICHS K, Feuerstein G, Davis J, Sirén A-L: Increase in Hippocampal Norepinephrine (NE) and Dopamine (DA) after Blockade of a2-Adrenoceptors. SOCIETY FOR NEUROSCIENCE, Abstracts Vol. 16, Part 1: 430, 1990
3. FRERICHS KU, Naveri L, Xu K, Hallenbeck JM, Feuerstein G, Davis JN, Sirén AL: Persistent Decrease in Hippocampal Norepinephrine Release Associated with Transient Forebrain Ischemia. SOCIETY FOR NEUROSCIENCE, Abstracts Vol. 17, Part 2:1085, 1991
4. Liu D, FRERICHS KU, Brenner M, Simpson IA, Hallenbeck JM: Regional Glut 1 and Glut 3 Glucose Transporter mRNA Expression in Ground Squirrels During Hibernation and Arousal. SOCIETY FOR NEUROSCIENCE, Abstracts Vol. 25, Part 2:1845, 1999
5. FRERICHS KU, Smith CB, Brenner M, DeGracia DJ, Krause GS, Marrone L , Dever T, Hallenbeck JM: Suppression of Cerebral Protein Synthesis Involves Inhibition of Protein Initiation and Elongation. SOCIETY FOR NEUROSCIENCE, Abstracts Vol. 25, Part 1:826, 1999

Media Reports/Newspaper Articles

1. (Stroke and Hibernation)February 1993 Boston Globe,(AP), Philadelphia Enquirer, Chicago Tribune, etc.
2. August 1994 Frankfurter Allgemeine Zeitiung (German National Daily Newspaper)
3. December 1997 Science News
4. February 1998 Der Spiegel (German Weekly News Magazine)

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