Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer's disease

Abstract

Neurodegenerative disorders such as Alzheimer’s disease (AD) are characterized by the loss of neurotrophic factors and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity. Cerebrolysin™, a peptide mixture with neurotrophic-like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice over expressing the amyloid precursor protein (APP). However it is unclear how long lasting the beneficial effects of Cerebrolysin™ are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption. The objective of the present study was to investigate the consequences of interrupting Cerebrolysin™ treatment (“wash-out” effect) 3 and 6 months after the completion of a 3-month treatment period in APP tg mice. We demonstrate that in APP tg mice, Cerebrolysin™-induced amelioration of memory deficits in the water maze and reduction of neurodegenerative pathology persist for 3 months after treatment interruption, however these effects dissipate 6 months following treatment termination. Immunohistochemical analysis demonstrated that the decrease in neocortical and hippocampal amyloid plaque load observed in Cerebrolysin™ treated APP tg mice immediately following treatment was no longer apparent at 3 months after treatment interruption indicating that the beneficial effects of Cerebrolysin™ at this time point were independent of its effect on amyloid-beta deposition. In conclusion the results demonstrate that effects of Cerebrolysin™ persist for a significant period of time following treatment termination and suggest that this prolonged effect may involve the neurotrophic factor-like activity of Cerebrolysin™.

Lower Cerebrospinal Fluid Concentration of Brain-Derived Neurotrophic Factor Predicts Progression from Mild Cognitive Impairment to Alzheimer’s Disease

“…Lithium administration can also increase BDNF levels and exert additional neuroprotective effects in patients at risk of AD (de Sousa et al 2011). Cerebrolysin, a peptide mixture with neurotrophic properties, was also shown to improve cognitive deficits and amyloid burden in animal models of AD (Rockenstein et al 2011). In a clinical trial, cerebrolysin improved cognitive function in patients with mild-to-moderate AD (Alvarez et al 2011).…”

Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease

“…For these experiments, hAPP tg mice expressing mutated (Swedish K670M/N671L, London V717I) human (h) APP751 under the control of the mouse (m) Thy‐1 promoter (mThy1‐hAPP751; line 41; Rockenstein et al, 2001) were used. These mice have been extensively characterized (Rockenstein et al, 2003, 2005, 2011b; Spencer et al, 2008; Crews et al, 2010, 2011; Havas et al, 2011), and we have previously shown that they display loss of synaptic contacts, defects in neurogenesis, high levels of Aβ 1–42 production, early amyloid deposition, and behavioral deficits (Rockenstein et al, 2003, 2007a, b). These mice were chosen because they show histopathological and cognitive impairments at a much earlier age (beginning at 3 months) compared with other transgenic AD mouse models (Masliah and Rockenstein, 2000).…”

Cerebrolysin in the therapy of mild cognitive impairment and dementia due to Alzheimer's disease: 30 years of clinical use

“…142,157,164,166,179,[186][187][188][189][190] The expression of GLUT1 glucose transporter and the transport of glucose through the BBB were also enhanced by Cerebrolysin. 142,191,192 Finally, Cerebrolysin regulates the expression of caspases and other apoptosis/autophagyrelated factors [154][155][156][157]164,167,184,193,194 ; the levels of dendritic microtubule-associated protein-2 (MAP2) and of synaptic proteins involved in neuroplasticity [150][151][152][153]175,[194][195][196] ; and the activity of the sonic hedgehog signaling pathway, implicated in neurogenesis and neurorestoration. 197…”

“…Cerebrolysin reduces brain Aβ production, 151,195 and probably clearance, 198 and tau phosphorylation [150][151][152][153] ; attenuates neuroinflammation, counteracting the upregulation of TNF-α, IL-1β and, other inflammatory factors [157][158][159][160][161][162][163][164][165] ; stimulates the maturation, expression, and signaling of endogenous neurotrophic factors as NGF, BDNF, and IGF-1, and exerts neurotrophic-like effects [163][164][165][166][167][168][169][170][171][172][173][174][175][176] ; reduces intracellular oxidative and cytotoxic cascades [177][178][179][180][181][182][183][184][185] ; modulates synaptic transmission mediated by GABA and glutamate, and displays cholinotrophic activity 166,[170][171][172][186][187]…”