New insights in animal models of neurotoxicity-induced neurodegeneration

Abstract

The high prevalence of neurodegenerative diseases is an unintended consequence of the high longevity of the population, together with the lack of effective preventive and therapeutic options. There is great pressure on preclinical research, and both old and new models of neurodegenerative diseases are required to increase the pipeline of new drugs for clinical testing. We review here the main models of neurotoxicity-based animal models leading to central neurodegeneration. Our main focus was on studying how changes in neurotransmission and neuroinflammation, mainly in rodent models, contribute to harmful processes linked to neurodegeneration. The majority of the models currently in use mimic Parkinson's disease (PD) and Alzheimer's disease (AD), which are the most common neurodegenerative conditions in older adults. AD is the most common age-related dementia, whereas PD is the most common movement disorder with also cases of dementia. Several natural toxins and xenobiotic agents induce dopaminergic neurodegeneration and can reproduce neuropathological traits of PD. The literature analysis of MPTP, 6-OH-dopamine, and rotenone models suggested the latter as a useful model when specific doses of rotenone were administrated systemically to C57BL/6 mice. Cholinergic neurodegeneration is mainly modelled with the toxin scopolamine, which is a useful rodent model for the screening of protective drugs against cognitive decline and AD. Several agents have been used to model neuroinflammation-based neurodegeneration and dementia in AD, including lipopolysaccharide (LPS), streptozotocin, and monomeric C-reactive protein. The bacterial agent LPS makes a useful rodent model for testing anti-inflammatory therapies to halt the development and severity of AD. However, neurotoxin models might be more useful than genetic models for drug discovery in PD but that is not the case in AD where they cannot beat the new developments in transgenic mouse models. Overall, we should work using all available models, either in vivo, in vitro, or in silico, considering the seriousness of the moment and urgency of developing effective drugs.

Keywords: Alzheimer’s disease; Parkinson’s disease; experimental models; neurodegeneration; neuroinflammation; neurotoxic agents; neurotransmission.

Figure 1

Scheme of animal models of neurotoxicity-induced dopaminergic neurodegeneration. MPTP, rotenone, and 6-OHDA induce neurotoxic effects that mimic Parkinson’s disease signs. All agents cause loss of dopaminergic neurons. The most complete and reliable model is that induced by rotenone treatment of C57BL/6J mice, that shows the formation of Lewy body-like granules. See text for details. i.m., intramuscular; i.p. intraperitoneal; p.o. per os (oral); i.c., intracerebral (medial forebrain bundle or striatum); DA, dopaminergic; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease. Created with BioRender.com.

Figure 2

Scheme of animal models of neurotoxicity-induced cholinergic or neuroinflammatory changes leading to Alzheimer’s disease-like neurodegeneration. The cholinergic agent scopolamine is widely used as inducer of memory loss; it increases tau synthesis without increasing p-tau (effect represented by a dashed arrow) or Aß. LPS, streptozotocin and mCRP induce a neuroinflammatory response and mild amyloid and tau pathologies with increase of p-tau and Aß. See text for details. i.p. intraperitoneal; i.c.v., intracerebroventricular; i.c., intracerebral (hippocampus); AD, Alzheimer’s disease; Aβ, Amyloid beta; LPS, lipopolysaccharide; mCRP, monomeric C reactive protein. Created with BioRender.com.