Intrinsic neurons of fastigial nucleus mediate neurogenic neuroprotection against excitotoxic and ischemic neuronal injury in rat.
Electrical stimulation of the cerebellar fastigial nucleus (FN) elevates regional cerebral blood flow (rCBF) and arterial pressure (AP) and provides long-lasting protection against focal and global ischemic infarctions. We investigated which neuronal element in FN, perikarya or axons, mediates this central neurogenic neuroprotection and whether it also protects against excitotoxicity. In anesthetized rats, the FN was stimulated for 1 hr, and ibotenic acid (IBO) was microinjected unilaterally into the striatum. In unstimulated controls, the excitotoxic lesions averaged approximately 40 mm3. Stimulation of FN, but not dentate nucleus (DN), significantly reduced lesion volumes up to 80% when IBO was injected 15 min, 72 hr, or 10 d, but not 30 d, thereafter. In other rats, intrinsic neurons of FN or DN were destroyed by pretreatment with IBO. Five days later, the FN was stimulated, and 72 hr later, IBO was microinjected into the striatum. Lesions of FN, but not DN, abolished neuroprotection but not the elevations of rCBF and AP elicited from FN stimulation. Excitotoxic lesions of FN, but not DN, also abolished the 37% reduction in focal ischemic infarctions produced by middle cerebral artery occlusion. Excitation of intrinsic FN neurons provides long-lasting, substantial, and reversible protection of central neurons from excitotoxicity, as well as focal ischemia, whereas axons in the nucleus, probably collaterals of ramified brainstem neurons, mediate the elevations in rCBF, which do not contribute to neuroprotection. Long-lived protection against a range of injuries is an unrecognized function of FN neurons transmitted over pathways distinct from those regulating rCBF.
Glickstein
S B
SB
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, USA.
Golanov
E V
EV
Reis
D J
DJ
D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000502:physiology; D002529:Cerebellar Nuclei / Q000502:physiology*; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006400:Hematocrit; D007051:Ibotenic Acid / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D019194:Ischemic Preconditioning; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007051:Ibotenic Acid; D005947:Glucose