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Ciliary Neurotrophic Factor Prevents Degeneration of Adult Proc. Natl. Acad. Sci. USA Vol. 90, pp. 6315-6319, July 1993 Neurobiology Ciliary neurotrophic factor prevents degeneration of adult rat substantia nigra dopaminergic neurons in vivo (neuronal death/axotomy/trophic factor/tyrosine hydroxylase/Parkinson disease) THEO HAGG* AND SILVIO VARON Department of Biology, University of California, San Diego, La Joila, CA 92093-0601 Communicated by Dominick P. Purpura, March 29, 1993 (receivedfor review December 10, 1992) ABSTRACT We have investigated the neuroprotective ef- effect was seen for their transmitter enzyme, choline acetyl- fects of recombinant human ciliary neurotrophic factor transferase (ChAT). In the present study, we investigated in (CNTF) for injured dopaminergic neurons of the adult rat adult rats whether CNTF could also have protective effects substantia nigra compacta. Fourteen days after a unilateral for injured and degenerating dopaminergic neurons of the ansetion of the nigrostriatal pathway two-thirds of the substantia nigra compacta. neurons (identiffed by retograde labeling) had degenerated. In sharp contrast, 73% (a few cases, >90%) of this ceil loss was prevented by continuous infusion of CNTF close to the injured METHODS neurons. However, CNTF did not prevent the disappearance of Nigrostriatal Transection. Female Sprague-Dawley rats the transmitter-synthesizing enzyme tyrosine hydroxylase. (200 g; Bantin & Kingman, Fremont, CA; housed and cared Thus, CNTF has potent neurotrophic effects for injured adult for according to National Institutes of Health and U.S. rat dopaminergic substantia nigra neurons, whose degenera- Department of Agriculture guidelines) (n = 30) were anes- tion plays a major causative role in Parkinson disease. thetized with a mixture of ketamine (62.5 mg/kg), xylazine (3.25 mg/kg), and acepromazine (0.62 mg/kg) and received a During development of the peripheral nervous system, neu- complete, but discrete, transection of their right nigrostriatal rons become dependent for their survival and/or function on pathway about 1 mm from the rostral tip of the substantia neurotrophic factors, specialized proteins that can be sup- nigra (Fig. 1 A and B). The transection was performed by plied by the innervation territory (1, 2). The importance of stereotactically lowering a 0.3-mm-wide guidance needle such factors for the maintenance of mature as well as injured containing two thin wire knifes (a in Fig. 1A), to coordinates adult neurons of the central nervous system (CNS) has also medio-lateral 1.7 mm, rostro-caudal -3.6 mm, and dorso- been recognized, in particular the relationship between nerve ventral -9.0 mm, all from Bregma with the tooth bar set at growth factor (NGF) and cholinergic basal forebrain neurons -3.3 mm. After extrusion of the wires in the medio-lateral (3, 4). Injury of the CNS often causes degeneration of the plane, a 3-mm-wide, 3-mm-high transection slit (±100 Am axotomized neurons, resulting in their atrophy or death. It is thick in rostro-caudal extent) (hatched area in Fig. 1B) was still unresolved whether such degenerative changes are made through the nigrostriatal pathway by moving the micro- caused primarily by the interruption oftarget-derived trophic knife dorsally. The wires were then drawn back into the support or the injury itself (5), but they can largely be guidance needle and both were withdrawn from the brain, prevented by administration (substitution) of exogenous leaving beside the transection, only a cannulation tract. To trophic factors (3, 4). establish an initial time course of neuronal loss, some Another type oftrophic factor, named ciliary neurotrophic transected animals were allowed to survive for 7 (n = 3), 14 factor (CNTF), was shown in vitro to have several biological (n = 4), or 28 (n = 3) days postlesion. activities for neurons and glial cells, including promotion of 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine survival by several types of developing peripheral nervous (DiI) Retrograde Labeling. In 10 of the remaining rats, sub- system and CNS neurons (6-11). CNTF has recently been stantia nigra neurons projecting to the neostriatum were purified, cloned, and sequenced and the human gene has been retrogradely labeled 12 days before unilateral nigrostriatal expressed in bacteria and insect cells to produce recombinant transection by injecting bilaterally the fluorescent tracer DiI protein in large enough quantities for in vivo investigations (Molecular Probes) with a 200-,um tip glass needle placed on (12-17). On the basis of its amino acid sequence, predicted a Hamilton syringe into six stereotactically defined tracts per tertiary structure, and type of receptors, CNTF is now striatum (0.3% in l%o ethanol/phosphate-buffered saline; 2 viewed as a member of the a-helical cytokine superfamily, ,ul each tract). DiI labeling has been shown not to affect which includes leukemia inhibitory factor, interleukin 6, survival of neurons in vitro and in vivo and remains robustly granulocyte colony-stimulating factor, and oncostatin M (18, detectable for up to 9 months in vivo without leakage to other 19). In vivo, purified CNTF can protect spinal motor neurons cells (24, 25). Its retrograde transport capability is based in ofdeveloping chickens against developmental neuronal death large part on passive diffusion through association with (20, 21) and facial motor neurons ofthe neonatal rat after their lipids, including cellular membranes, and results in the "fill- axotomy (22). We have recently shown in the adult rat in vivo ing" or labeling of the neuronal cell body and all processes. that CNTF can almost completely prevent the axotomy- CNTF Infusion. In these 10 rats, immediately after transec- induced degeneration ofcholinergic as well as noncholinergic tion, a 0.3-mm-wide metal infusion cannula was stereotacti- medial septum neurons (23). However, although CNTF pre- cally implanted and its tip was positioned 0.5 mm caudal to vented reduction ofcell body size and loss ofthe low-affinity the transection, directly into the brain parenchyma and just NGF receptors in these cholinergic neurons, no protective Abbreviations: ChAT, choline acetyltransferase; CNS, central ner- vous system; CNTF, ciliary neurotrophic factor; DiI, 1,1'- The publication costs ofthis article were defrayed in part by page charge dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine; NGF, nerve payment. This article must therefore be hereby marked "advertisement" growth factor; TH, tyrosine hydroxylase. in accordance with 18 U.S.C. §1734 solely to indicate this fact. *To whom reprint requests should be addressed. 6315 Downloaded by guest on September 29, 2021 6316 Neurobiology: Hagg and Varon Proc. Natl. Acad. Sci. USA 90 (1993) C 720 SNC -::-i24 XVyTA/'SNR FIG. 1. Sagittal (A) and coronal (B) views of the adult rat brain illus- trating the extent of the nigrostriatal 1080 - -36 transection and the position of the -- / infusion cannula (b in A). SN, sub- stantianigra;NS,neostriatum;ic,in- t ". ,' / ~~~~~~ternalcapsule; nsp, nigrostriatalpath- way. (C) Illustration of the borders used to define the substantia nigra compacta (SNC: neuron group A9; shaded and outlined by broken lines; 1440 48 left side is medial). VTA, ventral ~- - - -tegmental area, group A10; SNR, A - . , substantia nigra reticulata; SNL, lat- A8 :-t i / -eralis; 3, oculomotornerve. Numbers -~~~~;i/- on the left = distance from rostral \->t ~-- <: /~ pole of substantia nigra; numbers on the right = section number. Boxed area in section 12 = Fig. 2. rostral to the substantia nigra (Fig. 1A). Each cannula was (1:30,000) in TBS/serum/Triton X-100, 1.5 hr with goat connected to an Alzet 2002 mini-osmotic pump (Alza; partly anti-rabbit IgG (Vector Laboratories) in TBS/serum, 1.5 hr coated with paraffin to reduce the flow rate from 0.5 to 0.2 with avidin biotin complex (ABC Elite, Vector Laboratories) 1./hr) by a coiled reservoir (26). The reservoir was filled with in TBS, and, finally, 10 min with a mixture of 0.04% 3'3- vehicle (artificial cerebrospinal fluid with 1 mg of rat serum diaminobenzidine tetrahydrochloride/0.06% NiCl2/0.02% albumin per ml; Sigma A-6272) (n = 4) or vehicle containing H202 in Tris*HCl. In between steps, sections were washed for recombinant human CNTF (5 x 103 Trophic Units/day or 1.5 3 x 10 min in TBS. Stained sections were mounted on pg/day) (n = 6) for a 14-day infusion. Two different batches gelatin-subbed glass slides, air-dried, incubated for 30 sec in ofCNTF were used (n = 3 each) and were produced, purified, 0.005% OS04, dehydrated in ethanol, cleared in xylene, and characterized, and assayed for biological activity as de- coverslipped in Permount. After analysis and photography, scribed in detail elsewhere (23). In a pilot study, rats without these sections were rehydrated and stained with cresyl violet DiI labeling had received 14-day infusions with vehicle (n = (Nissl staining). For each animal the completeness of the 5) or CNTF (n = 5). In addition, 3 normal animals were used. lesion was evidenced in sections rostral to the transection by Histology and Analysis. After their respective survival the absence of TH-positive fibers in the region of the ipsi- times the animals were anesthetized again and transcardially lateral nigrostriatal tract, medial forebrain bundle, and neo- perfused with 75 ml ofcold phosphate-buffered saline and 250 striatum. For the counting of substantia nigra neurons on ml of cold 4% paraformaldehyde in 0.1 M phosphate buffer both sides ofthe brain, the compacta regions were defined by (pH 7.4), and their brains were postfixed for 16 hr and then the distribution of the TH- or DiI-positive neurons and a set cryoprotected in 30%o sucrose for 16-24 hr. Symmetrical of clear anatomical landmarks/boundaries (ref. 28; Fig. 1C). 30-,um-thick coronal sections were cut on a freezing micro- The number of TH-immunopositive or DiI-labeled compacta tome from the brain immobilized in a standardized position in neurons having a maximal cell body diameter .10 ,um was the plane of the Paxinos and Watson atlas (27).
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