Insulin-Like Growth Factor-1 Promotes Synaptogenesis Signaling, a Major Dysregulated Pathway in Malformation of Cortical Development, in a Rat Model

Abstract

Malformation of cortical development (MCD) is one of the main causes of intractable epilepsy in childhood. We explored a treatment based on molecular changes using an infant rat model of methylazoxymethanol (MAM)-induced MCD established by injecting MAM at gestational day 15. The offspring were sacri ced on postnatal day (P) 15 for proteomic analysis, which revealed signi cant downregulation in the synaptogenesis signaling pathway in the cortex of MCD rats. Recombinant human insulin-growth factor-1 (rhIGF-1) was injected from P12 to P14 twice daily and the effect of IGF1 on Nmethyl-D-aspartate (NMDA)-induced spasms (15 mg/kg of NMDA, i.p.) was tested; the onset of P15 single spasm was signi cantly delayed (p = 0.002) and the number of spasms decreased (p < 0.001) in rhIGF1-pretreated rats (n = 17) as compared to those in VEH-treated rats (n = 18). Electroencephalographic monitoring during spasms showed signi cantly reduced spectral entropy and event-related spectral dynamics of fast oscillation in rhIGF-1 treated rats. Magnetic resonance spectroscopy of the retrosplenial cortex showed decreased glutathione (GSH) (p = 0.039) and signi cant developmental changes in GSH, phosphocreatine (PCr), and total creatine (tCr) (p = 0.023, 0.042, 0.015, respectively) after rhIGF1 pretreatment. rhIGF1 pretreatment signi cantly upregulated expression of cortical synaptic proteins such as PSD95, AMPAR1, AMPAR4, NMDAR1, and NMDAR2A (p < 0.05). Thus, early rhIGF-1 treatment could promote synaptic protein expression, which was signi cantly downregulated by prenatal MAM exposure, and effectively suppress NMDA-induced spasms. Early IGF1 treatment should be further investigated as a therapeutic strategy in infants with MCD-related epilepsy.

Bioregenerative Applications of the Human Mesenchymal Stem Cell- Derived Secretome: Part-I

“…The secretome includes components involved in oxygen homeostasis regulation [108]. For example, TRX, Cys C, PRDX1, HSP27 and prolyl 4-hydroxylase help neutralize oxidatively reactive factors [79,[109][110][111][112][113][114]. This process is important in preventing oxidative stress that induces cell death and harms regeneration potential [109].…”

“…TRX promotes hippocampal neurogenesis [114]. N-cadherin promotes neural interactions with Schwann cells [111]. SEM7A, GDN and BASP-1 promote neurite outgrowth and axon guidance [114].…”

The Role of Insulin-like Growth Factor I in Mechanisms of Resilience and Vulnerability to Sporadic Alzheimer’s Disease

“…Among them, synapse loss is considered a major structural disturbance associated with cognitive deterioration in sAD [55]. Thus, IGF-I is involved in physiological synaptogenesis during development [56], in adult brains [57], and in synapse repletion after an insult [58]. Importantly, dendritic spines, a major site of cortical synapses, provide AD resilience [46], while IGF-I promotes dendritogenesis [59] and is intricately involved in synaptic physiology [60,61].…”