FURUKAWA Shoei GIFU PHARMAC.COLL., PROFESSOR, 薬学部, 教授 (90159129)
IBUKI Takae KYOTO PREF.UNIV., SCH.MEDICINE, ASSIS. PROFESSOR, 大学院, 講師 (90232587)
TSUKAHARA Masato YAMAGUCHI UNIV., SCH.MEDICINE, PROFESSOR, 医学部, 教授 (20136188)
OKANO Kozue YAMAGUCHI UNIV., SCH.MEDICINE, ASSOC. PROFESSOR, 医学部, 助教授 (50160693)
MATSUI Tomohiro YAMAGUCHI UNIV., SCH.MEDICINE, RES.ASSOSIATE, 医学部, 助手 (50314828)
櫻井 雅浩 東北大学, 大学院・胸部外科, 助手 (80344654)
|Budget Amount *help
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2003: ¥4,500,000 (Direct Cost: ¥4,500,000)
The neuronal regeneration of the peripheral-spinal cord sensory system in pathological pain after peripheral nerve injury has recently focused. However, there are no report concerning with either bone marrow stromal cell (BMSc) transplantation or trophic factor treatment for regeneration of cellular and functional derangements. We investigated the possibility of regeneration of spinal cord neurons of pathological pain using well-established rat model, which is known that the excessive release of glutamate and sP initiate perturbation of intracellular-nucleus processing resulting in increased Ca2+. In addition, we investigated possibilities for treatment by BMSc transplantation into spinal cord and synthesis of nerve growth factor by 4 methyl cathechol amine (4-MC).
The rats were divided into following two studies, BMSc and 4-MC study, respectively. In BMSc study, rats were subjected to spinal cord injury by completion and touch-evoked allodynia combined with astrocyte growing after BMSc
implantation (cultured neruspheas). In 4-MC study, the neuropathic pain was produced by legation of left sciatic nerve. The pain response (thermal hyperalgesia) combined with c-fos expression, apoptosis (TUNEL), and GFAP (astrocyte) at spinal cord were measured after nerve injury. For the treatment, (1) 4-MC, (2) magnetic field stimulation (MFS), (3) N-type Ca entry blocker, combined with anti-NGF, was respectively administered.
After transplantation of intrathecal BMSc one fourth of rats can gait and pain sensation was improved. In these improved animals, astrocyte growing was evident at both ventral and dorsal horn of spinal cord. On the other hands, after sciatic nerve injury, rats showed thermal hyperalgesia accompanied with increased spinal glutamate release during 5-10 days and that was enhanced with time. There were c-foes protein expression and apoptosis of superficial layer of spinal cord during early state of the hyperalgesia followed by the necrosis of the laminate 3-4 (interneuron). In decreased pain sensation animals appeared astrocyte growing at around Rexed III where is selectively damaged neurons after nerve injury. 4-MC significantly improved neuropathic pain associated with decreased incidences of c-foes, apoptosis, necrosis, and GFAP immunoreactivity of spinal cord neurons. 4-MC administration, which brings about the synthesis induction of the Brain derivated trophic factor and NGF that it attenuates the spinal glutamate release, and intracellular signaling including c-foes and that, suppresses these histopathological changes.
Based on present study, we demonstrated that possible improvement of pain sensation by peripheral nerve injury by injecting BMSc and trophic factor. In these functional recovery, the regeneration of neuron and astrocytes in Rexed III of spinal cord where is known as velnerable region and causes pain facilitation as disinhibitiom mechanisms. Otherwise, the peripheral nerve growth factors induced by magnetic field stimulation in regeneration of spinal cord neurons and related to attenuation of sensory systems such that of pathological pain. For the conversion to chronic pain, it was indicated that the dysfunction of the interneuron was concerned, and promotes further understand mechanisms of the nerve - immune network. It proves application of bone marrow stromal cells and trophic factor treatments to the functional recovery in the clinical situation As future direction, it will be needed to confirm safety of transplantation for possible treatment for neuropathic pain. Less