Recombinant AAV8-mediated intrastriatal gene delivery of CDNF protects rats against methamphetamine neurotoxicity

Abstract

Methamphetamine (METH) exerts significant neurotoxicity in experimental animals and humans when taken at high doses or abused chronically. Long-term abusers have decreased dopamine levels, and they are more likely to develop Parkinson's disease (PD). To date, few medications are available to treat the METH-induced damage of neurons. Glial cell line-derived neurotrophic factor (GDNF) has been previously shown to reduce the dopamine-depleting effects of neurotoxic doses of METH. However, the effect of cerebral dopamine neurotrophic factor (CDNF), which has been reported to be more specific and efficient than GDNF in protecting dopaminergic neurons against 6-OHDA toxicity, in attenuating METH neurotoxicity has not been determined. Thus, the present study aimed to evaluate the neuroprotective effect of CDNF against METH-induced damage to the dopaminergic system in vitro and in vivo. In vitro, CDNF protein increased the survival rate and reduced the tyrosine hydroxylase (TH) loss of METH-treated PC12 cells. In vivo, METH was administered to rats following human CDNF overexpression mediated by the recombinant adeno-associated virus. Results demonstrated that CDNF overexpression in the brain could attenuate the METH-induced dopamine and TH loss in the striatum but could not lower METH-induced hyperthermia.

Delayed Treatment of Capsaicin Produces Partial Motor Recovery by Enhancing Dopamine Function in MPP+-lesioned Rats via Ciliary Neurotrophic Factor

“…A reduction in apomorphine-induced rotational asymmetry and an increase in striatal DA levels were achieved by intranigral injection of adenoviral vector expressing GDNF (Ad-GDNF) at 10 weeks post 6-OHDA [27] or by intrastriatal injection of Ad-GDNF at 4 weeks post 6-OHDA [28]. Intrastriatal injection of adeno associated viral vector expressing CDNF (AAV8-CDNF) resulted in the reduction of apomorphine-induced rotational asymmetry and elevation of striatal DA levels at 5 weeks post 6-OHDA [29]. These studies also demonstrated that behavioral recovery is correlated with NTFs-induced trophic changes (restoration) of DA neurons.…”

“…These studies also demonstrated that behavioral recovery is correlated with NTFs-induced trophic changes (restoration) of DA neurons. The number of TH + cells in the SN and the density of TH + fibers in the STR were significantly increased after intrastriatal injection of an adenoviral vector expressing GDNF (Ad-GDNF) at 4 weeks post 6-OHDA [28] or of adeno associated viral vector expressing CDNF (AAV8-CDNF) at 5 weeks post 6-OHDA [29]. In contrast, results obtained from complete 6-OHDA lesioned rats indicated that GDNF infusion decreased apomorphine-induced rotation without nigrostriatal DA neuron recovery (neurorestoration) [30].…”

Computationally Guided Intracerebral Drug Delivery via Chronically Implanted Microdevices

“…A flowchart of COMMAND is shown in Figure S4, along with examples of stereotaxic coordinates used by prior studies in Figure S5 (Aoi et al, 2000;Bilang-Bleuel et al, 1997;Cederfjä ll et al, 2015;Hattori et al, 1998;Horellou et al, 1994;Kilbourn et al, 1997;Kirik et al, 2000;Luo et al, 1999;Mandel et al, 1998;Rodrigues et al, 2003;Sacaan et al, 1991;Shults et al, 1996;Wang et al, 2017aWang et al, , 2017bZaczek et al, 1980).…”

Protection of dopamine neurons by CDNF and neurturin variant N4 against MPP+ in dissociated cultures from rat mesencephalon

“…CDNF, along with mesencephalic astrocyte-derived neurotrophic factor (MANF), is part of a recently discovered family of NTFs [ 16 ] that appear to be at least as potent as the well-studied GDNF against certain toxins [ 17 , 18 ], although acting via a distinct mechanism [ 19 ]. CDNF increases survival in a catecholaminergic cell line, PC12 cells, from cell death induced by either the DA neurotoxin 6-hydroxydopamine (6-OHDA) [ 20 , 21 ] or methamphetamine [ 22 ]. The NTF also protects DA neurons when administered prior to 6-OHDA in both rats [ 22 – 25 ] and nonhuman primates [ 18 ] or to MPTP-treated mice [ 26 ].…”

“…CDNF increases survival in a catecholaminergic cell line, PC12 cells, from cell death induced by either the DA neurotoxin 6-hydroxydopamine (6-OHDA) [ 20 , 21 ] or methamphetamine [ 22 ]. The NTF also protects DA neurons when administered prior to 6-OHDA in both rats [ 22 – 25 ] and nonhuman primates [ 18 ] or to MPTP-treated mice [ 26 ].…”