Dubious -
So I am in fact the monkey's uncle. I should have tried "spinal" along with "spine," I suppose I assumed the search engine would have looked for close variations of any of the terms, as PubMed usually does. (As in "Did you mean ____?" and then it proceeds to give you the search output as though that's what you intended in the first place. My luck I had to post the existence of a negative the one time PubMed didn't help me out.) When I just ran "pregnenolone spinal rat" i got not only the article in question, but 32 others. Indeed, "Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury," Guth L, Zhang Z, Roberts E,
Proc Natl Acad Sci USA, 1994 Dec 6;91(25):12308-12 was 31st on the list. Apologies to Dr. Tennant.)
And if you're looking for amelioration of pain, check out No. 5 on the list:
"Biochemical and functional evidence for the control of pain mechanisms by dehydroepiandrosterone endogenously synthesized in the spinal cord," Kibaly C, Meyer L, Patte-Mensah C, Mensah-Nyagan AG,
FASEB J. 2008 Jan;22(1):93-104. Epub 2007 Aug 24, free full text at
http://www.fasebj.org/cgi/content/full/22/1/93
Institut des Neurosciences Cellulaires et Intégratives, Unité Mixte de Recherche 7168/LC2-Centre National de la Recherche Scientifique, Université Louis Pasteur, Département Nociception et Douleur, Strasbourg, France.
And here's the abstract:
We investigated the role and mechanism of action of dehydroepiandrosterone (DHEA) produced by the spinal cord (SC) in pain modulation in sciatic-neuropathic and control rats. Real-time polymerase chain reaction (PCR) after reverse transcription revealed cytochrome P450c17 (DHEA-synthesizing enzyme) gene repression in neuropathic rat SC. A combination of pulse-chase experiments, high performance liquid chromatography (HPLC), and flow-scintillation detection showed decreased DHEA biosynthesis from pregnenolone in neuropathic SC slices. Radioimmunoassays demonstrated endogenous DHEA level drop in neuropathic SC. Behavioral analysis showed a rapid pronociceptive and a delayed antinociceptive action of acute DHEA treatment. Inhibition of DHEA biosynthesis in the SC by intrathecally administered ketoconazole (P450c17 inhibitor) induced analgesia in neuropathic rats. BD1047 (sigma-1 receptor antagonist) blocked the transient pronociceptive effect evoked by acute DHEA administration. Chronic DHEA treatment increased and maintained elevated the basal nociceptive thresholds in neuropathic and control rats, suggesting that androgenic metabolites generated from daily administered DHEA exerted analgesic effects while DHEA itself (before being metabolized) induced a rapid pronociceptive action. Indeed, intrathecal administration of testosterone, an androgen deriving from DHEA, caused analgesia in neuropathic rats. Together, these molecular, biochemical, and functional results demonstrate that DHEA synthesized in the SC controls pain mechanisms. Possibilities are opened for pain modulation by drugs regulating P450c17 in nerve cells.
And this, coming in at No. 9 on the search:
"Neurogenic pain and steroid synthesis in the spinal cord," Patte-Mensah C, Kibaly C, Boudard D, Schaeffer V, Béglé A, Saredi S, Meyer L, Mensah-Nyagan AG,
J Mol Neurosci. 2006;28(1):17-31.
Institut des Neurosciences Cellulaires et Intégratives-Centre National de la Recherche Scientifique, Université Louis Pasteur, 67084 Strasbourg Cedex, France.
The spinal cord (SC) is a biosynthetic center for neurosteroids, including pregnenolone (PREG), progesterone (PROG), and 3alpha/5alpha-tetrahydroprogesterone (3alpha/5alpha-THP). In particular, an active form of cytochrome P450 sidechain cleavage (P450scc) has been localized in sensory networks of the rat SC dorsal horn (DH). P450scc is the key enzyme catalyzing the conversion of cholesterol (CHOL) into PREG, the rate-limiting step in the biosynthesis of all classes of steroids. To determine whether neurosteroidogenesis might be involved in the pivotal role played by the DH in nociception, effects of neurogenic pain provoked by sciatic nerve ligature were investigated on P450scc expression, cellular distribution, and activity in the SC. P450scc mRNA concentration was threefold higher in the DH of neuropathic rats than in controls. The nerve ligature also increased the density of P450sccpositive neuronal perykarya and fibers in the ipsilateral DH. Incubation of spinal tissue homogenates with [3H]CHOL revealed that the amount of newly synthesized [3H]PREG from [3H]CHOLwas 80% higher in the DH of neuropathic rats. Radioimmunoassays showed an increase of PREG and 3alpha/5alpha-THP concentrations in neuropathic rat DH. The upregulation of PREG and 3alpha/5alpha-THP biosynthesis might be involved in endogenous mechanisms triggered by neuropathic rats to cope with the chronic pain state. 3alpha/5alpha-THP formation from PREG can also generate PROG, which decreases sensitivity to pain and protects nerve cells against degeneration. Because apoptotic cell death has been demonstrated in the DH during neuropathic pain, activation of neurosteroidogenesis in spinal tissues might also be correlated to the neuroprotective role of steroids in the SC.
PMID: 16632873 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum
Finally, when you just ask for related articles to "Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury," you get lots of cool stuff, e.g.:
"Combined treatment with neurotrophin-3 and
LSD facilitates behavioral recovery from double-hemisection spinal injury in neonatal rats," Arvanian VL, Manuzon H, Davenport M, Bushell G, Mendell LM, Robinson JK, J Neurotrauma, 2006 Jan;23(1):66-74.
Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, New York 11794-5230, USA.
We explored functional recovery in two spinal cord injury models following a novel combination treatment (NT-3 + LSD). One group of rats received a staggered double hemisection (DH) at postnatal day 2 (P2) of the left hemicord at T11 and the right hemicord at T12. Another group received complete transection (CT) at T11 on P2. A third group was sham operated. Each of these groups was also treated with the drug combination. Drugs were administered intrathecally above the lesion during surgery, and again s.c. at P4, P6, P8, and P10. Intracellular recording in an in vitro spinal cord preparation at P10-P12 in DH rats revealed weak polysynaptic connections to lumbar motoneurons through the injury region, but only in those receiving NT-3 + LSD; NT-3 or LSD alone had no effect. In behavioral experiments, the frequency of rearing in an open field and hindlimb kicks during swimming was assessed every 3-4 days from P9 to P58. Both CT and DH injury severely impaired rearing and hindlimb kicking during swimming. DH rats treated with NT-3 + LSD showed significantly more kicks during swimming than untreated DH or CT rats and treated CT rats beginning as early as P9 and lasting through the duration of testing. Rearing behavior was also improved by treatment but beginning only in the 3rd postnatal week, the time at which it normally develops. Rearing frequency reached sham control levels by P40. Our results suggest this combination treatment may be a promising new strategy for facilitating recovery from moderate spinal cord injury.
PMID: 16430373 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum
As well as:
"A select combination of neurotrophins enhances neuroprotection and functional recovery following spinal cord injury," Sharma HS,
Ann N Y Acad Sci. 2007 Dec;1122:95-111.
Department of Surgical Sciences, University Hospital, Uppsala University, SE-75421 Uppsala, Sweden.
sharma@surgsci.uu.se
Previously, we have shown that topical application of brain-derived neurotrophic factor (BDNF) or insulin-like growth factor 1 (IGF-1) given within 5 to 30 min after a focal trauma to the rat spinal cord attenuates spinal cord injury (SCI)-induced breakdown of the blood-spinal cord barrier (BSCB), edema formation, motor dysfunction, and cell injury. This investigation was undertaken to find out whether a combination of select neurotrophins (BDNF, glial cell line-derived neurotrophic factor [GDNF], neurotrophin 3 [NT-3], or nerve growth factor [NGF]) will further enhance the neuroprotective efficacy of growth factors in SCI. The neurotrophins (0.1-1 microg/10 microL in phosphate-buffered saline) were applied 30, 60, or 90 min after injury topically over the traumatized spinal cord either alone or in combination. The SCI was performed by making a unilateral incision into the right dorsal horn of the T10-T11 segment under Equithesin anesthesia. The rats were allowed to survive 5 h after trauma. Topical application of BDNF, GDNF, or NGF 30 min after SCI in high concentration (0.5 microg and 1 microg) significantly improved the motor functions and reduced the BSCB breakdown, edema formation, and cell injury seen at 5 h. These beneficial effects of neurotropins were absent when administered separately either 60 or 90 min after SCI. However, a combination of BDNF and GDNF (but not with NT-3 or NGF) given either 60 or 90 min after SCI significantly reduced the motor dysfunction and spinal cord pathology at 5 h. These novel observations suggest that a select group of neurotrophins in combination have potential therapeutic value for the treatment of SCI in clinical situations.
PMID: 18077567 [PubMed - indexed for MEDLINE
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum
Finally, if there's any need to be reminded that
this too is rocket science, where jumping to any general conclusion is as inappropriate as in any other area, we have the following:
"Effects of progesterone on experimental spinal cord injury," Fee DB, Swartz KR, Joy KM, Roberts KN, Scheff NN, Scheff SW,
Brain Res. 2007 Mar 16;1137(1):146-52. Epub 2007 Jan 3.
Department of Neurology, University of Kentucky Chandler Medical Center, Lexington, KY 40536, USA.
dbfee@email.uky.edu
Progesterone has been proposed to be protective to the central nervous system following injury. This study assessed progesterone supplementation in the setting of contusional spinal cord injury in male and female rats. Short-term (5 days of either 4 or 8 mg/kg progesterone) and long-term (14 days of either 8 or 16 mg/kg progesterone) therapy failed to show any significant alteration in locomotor functioning and injury morphometrics after 21 days. This study does not support progesterone as a potential therapeutic agent in spinal cord injury.
PMID: 17204255 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum
Thanks again for setting me strait.
Mike