IGF-1/IGF-R Signaling in Traumatic Brain Injury: Impact on Cell Survival, Neurogenesis, and Behavioral Outcome

Sounds like something useful for strokes also. But nothing will be done for at least 50 years because we have no one executing a stroke strategy, failure on a grand scale of all our stroke associations.
http://www.ncbi.nlm.nih.gov/pubmed/26269893

Madathil SK, Saatman KE.

Editors

In: Kobeissy FH PhD, editor.

Source

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press; 2015. Chapter 7.
Frontiers in Neuroengineering.

Excerpt

Growing interest in post-traumatic brain plasticity events has fueled investigations of therapeutic approaches that promote endogenous neurorepair. Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with critical roles in regulating brain plasticity mechanisms. This chapter summarizes literature related to how expression of IGF-1 and its signaling components are altered after traumatic brain injury (TBI). To understand the potential effects of changes in endogenous IGF-1, the major roles of IGF-1 in CNS function are reviewed, with attention to how these IGF-mediated events may impact the response to TBI. In light of the multiplicity of CNS functions mediated by IGF-1, supplementation of endogenous IGF-1 may provide neuroprotection and promote neuronal repair in the injured brain. Coupled with a handful of preclinical studies in TBI, a larger literature in other CNS injuries such as stroke, hypoxic ischemia and spinal cord injury demonstrates potential beneficial effects of IGF-1 following injury. TBI pathophysiology is multifaceted, including primary and secondary events. Primary injury results from the mechanical forces including acceleration, deceleration, and impact forces at the moment of injury, producing diffuse or focal pathology. This initial phase is characterized by tissue deformation, membrane depolarization, disruption of blood vessels and axons, ischemia, and cell membrane damage (Beauchamp et al., 2008; Dietrich et al., 1994; Gaetz, 2004). Secondary injury evolves from this early damage over a period of hours to days and even weeks to months, characterized by a complex network of biochemical events (Dikmen et al., 2009; Farkas and Povlishock, 2007; McIntosh et al., 1999). Excitatory amino acids and inflammatory cytokines released early in the secondary injury cascade lead to altered calcium homeostasis. Excessive intracellular calcium can signal various biochemical pathways initiating inflammation, free radical generation, and cytoskeletal damage. Increased calcium can activate proteases including calpains and caspases. Once activated, these proteases can cause widespread cell damage via cytoskeletal protein degradation and necrotic or apoptotic cell death pathways initiated within hours and continuing for days after brain injury. Secondary injury responses ultimately culminate in white matter damage and neurodegeneration contributing to behavioral morbidity. In response to destructive events, the brain also has the capacity to promote cell repair through various compensatory mechanisms commonly referred to as neuroplasticity. Altered growth factor signaling, synaptogenesis, angiogenesis, neurogenesis, and gliogenesis are among these posttrauma brain remodeling events (Kernie and Parent, 2009; Schoch et al., 2012; Stein and Hoffman, 2003; Yu et al., 2008). Expression and release of endogenous neurotrophic factors is altered by various forms of central nervous system (CNS) injuries including TBI. An increase in their expression is considered as one of the mechanisms to promote neuroprotection and neurorepair after damage (Guan et al., 2003). After TBI, expression of growth factors such as neurotrophin 4/5, nerve growth factor, basic fibroblast growth factor, brain-derived neurotrophic factor (BDNF), and IGF-1 are increased (Conte et al., 2003; Madathil et al., 2010; Royo et al., 2006). Many of these growth factors play important roles in brain development and thus their increased expression after brain injury can recapitulate many of the processes involved in brain growth, accelerating neuronal repair. Despite the improved understanding of TBI pathology, no therapeutic approach for treatment has yet been proved efficacious. Pharmacological approaches under research for TBI can be grouped as either neuroprotective or neuroreparative depending on their mode of action. Neuroprotective strategies that promote neuronal survival are focused mainly on attenuating acute damage from glutamate excitotoxicity, free radicals, or calcium influx. Neurorepair approaches promote neuroregeneration or neuroplasticity events. IGF-1, because of the multiplicity of its actions, provides a combined approach by attenuating cell death and promoting brain repair events (Aberg et al., 2000, 2006; Anderson et al., 2002; Lopez-Lopez et al., 2004).