Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease - PubMed (original) (raw)

Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease

P J Austin et al. Br J Pharmacol. 2010 Aug.

Abstract

Background and purpose: Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson's disease (PD). This study aimed to establish whether activation of pre-synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD.

Experimental approach: Broad-spectrum group III mGlu receptor agonists, O-phospho-l-serine (l-SOP) and l-2-amino-4-phosphonobutyrate (l-AP4), were assessed for their ability to inhibit KCl-evoked [(3)H]-d-aspartate release in rat nigral prisms or inhibit KCl-evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine-treated rats was assessed following intranigral injection of l-SOP and l-AP4. Finally, the neuroprotective effect of 7 days' supra-nigral treatment with l-AP4 was examined in 6-hydroxydopamine (6-OHDA)-lesioned rats.

Key results: l-SOP and l-AP4 inhibited [(3)H]-d-aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). l-SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l-SOP and l-AP4 into the SNpr reversed reserpine-induced akinesia. Following administration above the SNpc, l-AP4 provided neurochemical, histological and functional protection against 6-OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects.

Conclusions and implications: These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects.

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Figures

Figure 1

Figure 1

Effect of

l

-SOP (A,C,E) or

l

-AP4 (B,D,F) on 25 mM KCl-evoked [3H]-

d

-aspartate release in rat nigral tissue prisms. (A,B) Release profile showing effect of optimum concentration of

l

-SOP or

l

-AP4 on release evoked by the second KCl stimulus (S2). Horizontal bars indicate the periods of contact with KCl or drug/vehicle. Data are mean ± SEM (n = 3, from a single experimental run). (C,D) Graphs of S2/S1 ratio showing concentration-dependent effects of

l

-SOP or

l

-AP4 on [3H]-

d

-aspartate release. Data are mean ± SEM (n = 6); *P < 0.05 and **P < 0.01, significantly different from vehicle; ##P < 0.01 and ∞P < 0.05 significantly different from 3 and 100 µM

l

-AP4 respectively. (E,F) Effect of pre-incubation with the group III mGlu receptor antagonist, CPPG (100 µM) on responses to

l

-SOP (100 µM) or

l

-AP4 (30 µM). The presence (+) or absence (–) of drugs is indicated. Data are mean ± SEM (n = 6); ***P < 0.001 significantly different from other groups.

Figure 2

Figure 2

Effect of

l

-SOP on 100 mM KCl-evoked glutamate release in the rodent SNpr in vivo. (A) Release profile showing the effect of vehicle or

l

-SOP on release evoked by the second KCl stimulus, S2. Horizontal bars indicate the periods of contact with KCl or

l

-SOP/vehicle. (B) Graph of S2/S1 ratio showing concentration-dependent effect of

l

-SOP on glutamate release. In both cases, data are mean ± SEM (n = 4). *P < 0.05 significantly different from vehicle.

Figure 3

Figure 3

Effect of unilateral injection of

l

-SOP (A,C,E) or

l

-AP4 (B,D,F) in the SNpr on reversal of akinesia in the reserpine-treated rat. (A,B) Time-course of locomotor activity induced by the maximally effective dose of

l

-SOP or

l

-AP4. Data are mean ± SEM (n = 6); ***P < 0.001 significantly different from vehicle. (C,D) Effect of

l

-SOP or

l

-AP4 on rotational activity over 60 min. Data are mean ± SEM (n = 6). In (C), *P < 0.05 and **P < 0.01 significantly different from vehicle, #P < 0.05 significantly different from 250 nmol dose. In (D), ***P < 0.001 significantly different from vehicle and 3 nmol: #P < 0.05 significantly different from 30 and 100 nmol. (E,F) Effect of pretreatment with CPPG (75 nmol) on the rotational responses to

l

-SOP (750 nmol) or

l

-AP4 (300 nmol). Data are mean ± SEM (n = 6). ***P < 0.001 significantly different from vehicle pretreatment.

Figure 4

Figure 4

Effect of repeated

l

-AP4 treatment against 6-OHDA-induced (A) reduced contralateral paw use in the cylinder test at 4 days post-lesion, (B) reduced contralateral paw use in forehand or backhand adjusted stepping test at 6 days post-lesion and (C) increased amphetamine-induced ipsiversive rotations at 7 days post-lesion. Data are mean ± SEM (n = 9, vehicle; n = 6–7,

l

-AP4). *P < 0.05 and **P < 0.01, significantly different from (A) pre-lesion score or (B,C) vehicle.

Figure 5

Figure 5

Effect of repeated

l

-AP4 treatment against 6-OHDA-induced (A) loss of TH-positive cells in the SNpc in the lesion hemisphere, (B) reduction in TH levels in the lesion striatum and (D) reduction in DDC levels. Data are mean ± SEM (A,B) n = 10 for vehicle; n = 6–7 for

l

-AP4; (D) n = 10 for vehicle; n = 4,7 and 8 for increasing doses of

l

-AP4. **P < 0.01 and ***P < 0.001 significantly different from vehicle (one-way

anova

with a Bonferroni post hoc test). (C) Photomicrographs showing TH staining in the striatum and SNpc of animals treated with the optimum dose of

l

-AP4 (3 nmol) or vehicle; lesion side on right. Scale bar: 500 µm for striatum; 200 µm for SNpc.

Figure 6

Figure 6

Effect of pretreatment with 75 nmol CPPG or vehicle on the protection afforded by 3 nmol

l

-AP4 against 6-OHDA-induced (A) reduced contralateral paw use in the cylinder test at 4 days post-lesion, (B) reduced contralateral paw use in forehand or backhand adjusted stepping test at 6 days post-lesion, (C) increased amphetamine-induced ipsiversive rotations at 7 days post-lesion and (D) reduction in striatal dopamine content. _X_-axis labels: vehicle, vehicle treatment;

l

-AP4,

l

-AP4 treatment following vehicle pretreatment; CPPG +

l

-AP4,

l

-AP4 treatment following CPPG pretreatment. Data are mean ± SEM (n = 6, vehicle; n = 7

l

-AP4 and

l

-AP4 + CPPG). (A) *P < 0.05, significantly different from pre-lesion score (two-way

anova

and Bonferroni post hoc test). (B,C,D) *P < 0.05 and ***P < 0.001 significantly different from vehicle treatment and from CPPG pretreatment followed by

l

-AP4 (one-way

anova

with Bonferroni post hoc test).

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