6‐hydroxydopamine‐induced Parkinson's disease‐like degeneration generates acute microgliosis and astrogliosis in the nigrostriatal system but no bioluminescence imaging‐detectable alteration in adult neurogenesis

Abstract

Parkinson's disease is a slowly progressing neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra (SN), leading to severe impairment in motor and non-motor functions. Endogenous subventricular zone (SVZ) neural stem cells constantly give birth to new cells that might serve as a possible source for regeneration in the adult brain. However, neurodegeneration is accompanied by neuroinflammation and dopamine depletion, potentially compromising regeneration. We therefore employed in vivo imaging methods to study striatal deafferentation (N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[(123) I]iodophenyl)nortropane single photon emission computed tomography, DaTscan(™) ) and neuroinflammation in the SN and striatum (N,N-diethyl-2-(2-(4-(2-[(18) F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide positron emission tomography, [(18) F]DPA-714 PET) in the intranigral 6-hydroxydopamine Parkinson's disease mouse model. Additionally, we transduced cells in the SVZ with a lentivirus encoding firefly luciferase and followed migration of progenitor cells in the SVZ-olfactory bulb axis via bioluminescence imaging under disease and control conditions. We found that activation of microglia in the SN is an acute process accompanying the degeneration of dopaminergic cell bodies in the SN. Dopaminergic deafferentation of the striatum does not influence the generation of doublecortin-positive neuroblasts in the SVZ, but generates chronic astrogliosis in the nigrostriatal system.

Extensive exploration of a novel rat model of Parkinson's disease using partial 6‐hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

“…In this context, the recent development of noninvasive imaging methods in small animals gives the unique opportunity to follow at the same time a number of various parameters such as brain activity, neurotransmission, and neuroinflammation during the course of the disease, and the effects of potential treatments. In this field, positron emission tomography (PET) has already demonstrated its usefulness, particularly in 6‐hydroxydopamine (6‐OHDA) lesion models of PD in rodents (Casteels et al, ; Fricke et al, ; Molinet‐Dronda et al, ). Although these models have been well recognized and widely used, most use direct injections of the toxin into the SNpc or medial forebrain bundle (MFB), producing a rapid and massive (>90%) degeneration of DA neurons (Gubellini & Kachidian, ) that reflect late stages of PD (Glajch et al, ).…”

In vivo bioluminescence imaging of neurogenesis – the role of the blood brain barrier in an experimental model of Parkinson's disease

“…Stereotactic injections were performed as previously described (Fricke et al ., ). Briefly, female C57Bl6 ( n = 42) and Dcx‐Luc ( n = 25) mice (12–14 weeks of age) were anaesthetised with ketamine/xylazine (i. p.) and a stereotactic injection of 2 μL 5 mg/mL 6‐OHDA (Sigma‐Aldrich) in 0.01% ascorbic acid (Carl Roth, Karlsruhe, Germany) and 0.9% NaCl (Carl Roth) or vehicle (0.01% ascorbic acid in 0.9% NaCl) was performed into the left SN (coordinates in relation to bregma: lateral −1.5 mm, anterior‐posterior −3.0 mm, dorsal‐ventral −4.4 mm).…”

“…SPECT imaging was performed at 7 weeks post injection in 6‐OHDA ( n = 5) and vehicle ( n = 3) injected Dcx‐Luc mice that were followed longitudinally with BLI. Imaging and data analysis were performed as described previously (Fricke et al ., ). Briefly, animals were anaesthetised with 1.5% isoflurane (Abbott Animal Health, IL, USA) in 100% O 2 , the lateral tail vein was cannulated using a 26 Ga catheter (Vasculon Plus; BD, Heidelberg, Germany), 16 MBq [ 123 I]Ioflupane (N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐[ 123 I]iodophenyl)nortropane, DaTscan™, GE Healthcare, Chalfont St Giles, GB) were injected i. v. and a 15 min SPECT scan was conducted 60 min post injection (p.…”

“…To study the role of neurogenesis in brain injury and neurodegeneration, approaches using non‐invasive, longitudinal in vivo imaging are particularly attractive. Approaches enabling the study of adult neurogenesis non‐invasively include positron emission tomography (PET) with the tracer 3′‐deoxy‐3′‐[ 18 F]fluorothymidine ([ 18 F]FLT), Magnetic Resonance Imaging (MRI) with in situ iron oxide particle labelling or genetic MRI reporter genes, and optical imaging (bioluminescence and fluorescence) using viral vectors or transgenic animals for reporter gene delivery and expression (Couillard‐Despres et al ., ; Fricke et al ., ).…”

“…Altered rates of neurogenesis were observed in several neurologic disease models, for example, increased neurogenesis following cerebral ischemia and traumatic brain injury (Ruan et al ., ). In neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease (AD, PD, HD, respectively), several reports describe alterations in neurogenesis, varying from increased or unchanged (Fricke et al ., ) neurogenic rates, to decreased rates (Ruan et al ., ).…”