transforming-growth-factor-beta and Brain-Infarction

Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily. Over the last decade, GDNF has been shown to promote regenerative and restorative effects on dopaminergic neurons. Accumulating evidence also demonstrates that administration of GDNF to areas of ischemic brain injury limits cerebral infarction and reduces damage to motor functions in animal models of stroke. Neurotrophic factor and anti-apoptotic mechanisms, among others, have been proposed to underlie the therapeutic effects of GDNF. A major obstacle for GDNF therapy is the protein delivery to the brain, as well as its sustained bioavailability over time. Gene therapy and the use of viral vectors offer a technique for longevity of GDNF expression within the brain. In this review, we consider the risks and benefits of GDNF gene therapy as it relates to the treatment of stroke.

Topics: Animals; Apoptosis; Brain; Brain Infarction; Dopamine; Genetic Therapy; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Humans; Nerve Growth Factors; Neurons; Stroke; Transforming Growth Factor beta; Viruses

1. Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by using the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. 2. Over the last years, the cytokine termed Transforming Growth Factor-beta1 (TGF-beta1) has been found to be strongly up-regulated in the central nervous system following ischemia-induced brain damage. 3. Recent studies have shown a neuroprotective activity of TGF-beta1 against ischemia-induced neuronal death. In vitro, TGF-beta1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes 4. In addition, TGF-beta1 has been recently characterized as an antiapoptotic factor in a model of staurosporine-induced neuronal death through a mechanism involving activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) and a concomitant increase phosphorylation of the antiapoptotic protein Bad. 5. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.

Topics: Animals; Apoptosis; bcl-Associated Death Protein; Brain Infarction; Brain Ischemia; Carrier Proteins; Humans; Mitogen-Activated Protein Kinases; Neuroprotective Agents; Plasminogen Activator Inhibitor 1; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor β (TGF-β) is an anti-inflammatory cytokine and its role in hydrocephalus and stoke has been suggested. Tuberculous meningitis (TBM) is associated with exudates, stroke, hydrocephalus and tuberculoma, but the role of TGF-β has not been evaluated in relation to these changes.. To evaluate the cerebrospinal fluid (CSF) TGF-β level in the patients with TBM, and correlate these with clinical findings, MRI changes, paradoxical response and outcome at 6months.. TBM patients diagnosed on the basis of clinical, CSF and MRI criteria were prospectively included. The clinical details including duration of illness, seizures, focal motor deficit, Glasgow Coma Scale (GCS) score and stage of TBM were noted. Presence of exudate, hydrocephalus, tuberculoma and infarction in MRI was also noted. MRI was repeated at 3months and presence of paradoxical response was noted. Cerebrospinal fluid TGF-β was measured using ELISA on admission and repeated at 3months and these were compared with 20 controls.. TGF-β level was significantly higher in TBM compared to the controls (385.76±249.98Vs 177.85±29.03pg/ml, P<0.0001). TGF-β correlated with motor deficit, infarction and tuberculoma on admission but did not correlate with CSF abnormalities, drug induced hepatitis, paradoxical response and outcome. TGF-β level at 3months was significantly lower than the baseline but remained higher than the controls.. CSF TGF-β levels are elevated in TBM and correlate with infarction and tuberculoma.

Topics: Adolescent; Adult; Aged; Brain Infarction; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Transforming Growth Factor beta; Tuberculoma, Intracranial; Tuberculosis, Meningeal

Transplantation of mesenchymal stem cells (MSCs) has been shown to enhance the recovery of brain functions following ischemic injury. Although immune modulation has been suggested to be one of the mechanisms, the molecular mechanisms underlying improved recovery has not been clearly identified. Here, we report that MSCs secrete transforming growth factor-beta (TGF-β) to suppress immune propagation in the ischemic rat brain. Ischemic stroke caused global death of resident cells in the infarcted area, elevated the monocyte chemoattractant protein-1 (MCP-1) level, and evoked massive infiltration of circulating CD68+ immune cells through the impaired blood-brain barrier. Transplantation of MSCs at day 3 post-ischemia blocked the subsequent upregulation of MCP-1 in the ischemic area and the infiltration of additional CD68+ immune cells. MSC-conditioned media decreased the migration and MCP-1 production of freshly isolated immune cells in vitro, and this effect was blocked by an inhibitor of TGF-β signaling or an anti-TGF-β neutralizing antibody. Finally, transplantation of TGF-β1-silenced MSCs failed to attenuate the infiltration of CD68+ cells into the ischemic brain, and was associated with only minor improvements in motor function. These results indicate that TGF-β is key to the ability of MSCs to beneficially attenuate immune reactions in the ischemic brain. Our findings offer insight into the interactions between allogeneic MSCs and the host immune system, reinforcing the prospective clinical value of using MSCs in the treatment of neurological disorders involving inflammation-mediated secondary damage.

Topics: Animals; Antigens, CD; Blood-Brain Barrier; Brain Infarction; Calcium-Binding Proteins; Cell Movement; Cells, Cultured; Chemokine CCL2; Disease Models, Animal; Encephalitis; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Microfilament Proteins; Peroxidase; Rats; Rats, Sprague-Dawley; Time Factors; Transforming Growth Factor beta

The mechanisms that control the phagocytic activities of microglia and macrophages during disorders of the nervous system are largely unknown. In the present investigation, we assessed the functional role of transforming growth factor (TGF)beta2 in vitro and studied TGFbeta-2mRNA and protein expression in two CNS lesion paradigms in vivo characterized by fundamental differences in microglia/macrophage behaviour: optic nerve crush exhibiting slow, and focal cerebral ischemia exhibiting rapid phagocytic transformation. Furthermore, we used sciatic nerve crush injury as a PNS lesion paradigm comparable to brain ischemia in its rapid phagocyte response. In normal and degenerating optic nerves, astrocytes strongly and continuously expressed TGF-beta2 immunoreactivity. In contrast, TGF-beta2 was downregulated in Schwann cells of degenerating sciatic nerves, and was not expressed by reactive astrocytes in the vicinity of focal ischemic brain lesions during the acute phagocytic phase. In line with its differential lesion-associated expression pattern, exogenous TGF-beta2 suppressed spontaneous myelin phagocytosis by microglia/macrophages in a mouse ex vivo assay of CNS and PNS Wallerian degeneration. In conclusion, we have identified TGF-beta2 as a nervous system intrinsic cytokine that could account for the differential regulation of phagocytic activities of microglia and macrophages during injury.

Topics: Animals; Brain; Brain Infarction; Cells, Cultured; Down-Regulation; Female; Immunohistochemistry; Macrophages; Male; Mice; Microglia; Nerve Crush; Nervous System; Optic Nerve Injuries; Phagocytosis; Rats; Reverse Transcriptase Polymerase Chain Reaction; Sciatic Nerve; Transforming Growth Factor beta; Transforming Growth Factor beta2; Wallerian Degeneration