Differential regulation of FGF-2 in neurons and reactive astrocytes of axotomized rat hypoglossal nucleus. A possible therapeutic target for neuroprotection in peripheral nerve pathology

Despite the favorable treatment of cranial nerve neuropathology in adulthood, some cases are resistant to therapy leading to permanent functional impairments. In many cases, suitable treatment is problematic as the therapeutic target remains unknown. Basic fibroblast growth factor (bFGF, FGF-2) is involved in neuronal maintenance and wound repair following nervous system lesions. It is one of few neurotrophic molecules acting in autocrine, paracrine and intracrine fashions depending upon specific circumstances. Peripheral cranial somatic motor neurons, i.e. hypoglossal (XII) neurons, may offer a unique opportunity to study cellular FGF-2 mechanisms as the molecule is present in the cytoplasm of neurons and in the nuclei of astrocytes of the central nervous system. FGF-2 may trigger differential actions during development, maintenance and lesion of XII neurons because axotomy of those cells leads to cell death during neonatal ages, but not in adult life. Moreover, the modulatory effects of astroglial FGF-2 and the Ca+2-binding protein S100β have been postulated in paracrine mechanisms after neuronal lesions. In our study, adult Wistar rats received a unilateral crush or transection (with amputation of stumps) of XII nerve, and were sacrificed after 72 h or 11 days. Brains were processed for immunohistochemical localization of neurofilaments (NF), with or without counterstaining for Nissl substance, glial fibrillary acidic protein (GFAP, as a marker of astrocytes), S100β and FGF-2. The number of Nissl-positive neurons of axotomized XII nucleus did not differ from controls. The NF immunoreactivity increased in the perikarya and decreased in the neuropil of axotomized XII neurons 11 days after nerve crush or transection. An astrocytic reaction was seen in the ipsilateral XII nucleus of the crushed or transected animals 72 h and 11 days after the surgery. The nerve lesions did not change the number of FGF-2 neurons in the ipsilateral XII nucleus; however, the nerve transection increased the number of FGF-2 glial profiles by 72 h and 11 days. Microdensitometric image analysis revealed a short lasting decrease in the intensity of FGF-2 immunoreactivity in axotomized XII neurons by 72 h after nerve crush or transection and also an elevation of FGF-2 in the ipsilateral of glial nuclei by 72 h and 11 days after the two lesions. S100β decreased in astrocytes of 11-day-transected XII nucleus. The two-color immunoperoxidase for the simultaneous detection of the GFAP/FGF-2 indicated FGF-2 upregulation in the nuclei of reactive astrocytes of the lesioned XII nucleus. Astroglial FGF-2 may exert paracrine trophic actions in mature axotomized XII neurons and might represent a therapeutic target for neuroprotection in peripheral nerve pathology.