Table 2.
Effects of non-dopaminergic therapies in animal models.
| Drug class | Subclass | Effect in animal models | References |
|---|---|---|---|
| Adenosine receptor antagonists | A2A antagonists Preladenant, Istradefylline, SCH58261, SCH412348, MSX-3 | ↓ catalepsy in reserpine and haloperidol models | Mandhane et al., 1997; Kanda et al., 1998; Shiozaki et al., 1999; Ikeda et al., 2002; Salamone et al., 2008; Hodgson et al., 2009; Trevitt et al., 2009 |
| ↑ L-Dopa-induced contralateral turning behavior in 6-OHDA model | |||
| ↓ behavioral sensitization induced by L-Dopa | |||
| ↑ locomotion in MPTP and reserpine models | |||
| ↑ survival of DA neurons in 6-OHDA model | |||
| ↓ striatal DA nerve terminal loss and gliosis in MPTP model | |||
| Non-specific Caffeine, Theophylline, DMPX | ↓ catalepsy in reserpine and haloperidol models | Mandhane et al., 1997; Chen et al., 2001; Xu et al., 2002; Bishnoi et al., 2006; Kalda et al., 2006; Singh et al., 2009; Trevitt et al., 2009; Kachroo et al., 2010 | |
| ↑ survival of DA neurons in MPTP, paraquat and maneb models | |||
| NMDA Receptor Antagonists | NMDA Antagonists MK-801, Amantadine, Memantine, L-701,324, SDZ 220-58, Dextromethorphan, CPP | ↓ haloperidol-induced catalepsy | Carlsson and Carlsson, 1989; Graham et al., 1990; Mehta and Ticku, 1990; Loschmann et al., 1991; Turski et al., 1991; Zuddas et al., 1992a,b; Lange et al., 1993; Srivastava et al., 1993; Kaur and Starr, 1995; St-Pierre and Bedard, 1995; Marin et al., 1996; McAllister, 1996; Kaur et al., 1997; Konieczny et al., 1999; Dutra et al., 2002; Kelsey et al., 2004; Armentero et al., 2006 |
| ↓ akinesia in reserpine model | |||
| ↓ parkinsonian symptoms in MPTP model | |||
| ↑ stepping with contralateral paw in 6-OHDA model | |||
| ↑ contralateral circling in 6-OHDA model | |||
| ↓ dyskinesias in MPTP and 6-OHDA models | |||
| ↑ DA neuron survival, DA levels in MPTP and 6-OHDA models | |||
| ↑ efficacy of L-Dopa | |||
| NMDA-NR2B antagonists Ifenprodil, Traxoprodil, Co101244 | ↓ parkinsonian symptoms in MPTP model | Blanchet et al., 1999; Nash et al., 2000; Steece-Collier et al., 2000 | |
| ↑ efficacy of L-Dopa | |||
| ↓ haloperidol-induced catalepsy | |||
| ↓ appearance of LIDs | |||
| AMPA Receptor Antagonists | NBQX, Perampanel, Talampanel | ↑ contralateral rotations in 6-OHDA model | Klockgether et al., 1991; Loschmann et al., 1991, 1992; Wachtel et al., 1992; Konitsiotis et al., 2000 |
| ↓ reserpine-induced muscle rigidity | |||
| ↑ L-Dopa-induced reversal of motor deficits in MPTP and 6-OHDA models | |||
| ↓ LIDs in MPTP model | |||
| ↓ L-Dopa-induced AIMs | |||
| Topiramate | ↓ LIDs in MPTP model | Silverdale et al., 2005; Kobylecki et al., 2011 | |
| ↓ L-Dopa-induced AIMs in 6-OHDA model | |||
| ↓ rotarod performance in 6-OHDA model | |||
| Metabotropic Glutamate Receptor Antagonists | Group I Metabotropic | ↓ akinesia in 6-OHDA model | Kearney et al., 1997, 1998; Breysse et al., 2002, 2003; Coccurello et al., 2004; Kachroo et al., 2005; Vernon et al., 2005, 2007; Dekundy et al., 2006; Rylander et al., 2009; Price et al., 2010; Morin et al., 2013a,b |
| Glutamate Receptor Antagonists MPEP, MTEP, LY367386, Dipraglurant, AFQ056 | ↓ LIDs in 6-OHDA model | ||
| ↑ survival of DA neurons in 6-OHDA model | |||
| ↑ striatal DA in 6-OHDA model | |||
| Serotonin Receptor Agonists | 5-HT1A Agonists | ↓ LIDs in 6-OHDA and MPTP models | Carta et al., 2007; Munoz et al., 2008; Lindgren et al., 2010 |
| 8-OH-DPAT | ↓ activity of raphe-striatal neurons and extracellular DA release in 6-OHDA model | ||
| 5-HT1B Agonists | ↓ LIDs in 6-OHDA model | Carta et al., 2007; Lindgren et al., 2010 | |
| CP-94253 | ↓ activity of raphe-striatal neurons and extracellular DA release in 6-OHDA model | ||
| 5-HT1A/1B Agonists | ↓ LIDs in 6-OHDA model | Bezard et al., 2013 | |
| Eltoprazine | ↓ LIDs in MPTP model | ||
| ↓ LIDs in combination with amantadine | |||
| Adrenergic Receptor Antagonists | α2 Receptor Antagonists Yohimbine, Idazoxan, Fipamezole | ↓ L-Dopa-induced hyperkinesia in 6-OHDA model | Gomez-Mancilla and Bedard, 1993; Henry et al., 1998, 1999; Fox et al., 2001; Invernizzi et al., 2003; Savola et al., 2003; Johnston et al., 2010; Barnum et al., 2012 |
| ↓ expression of AIMs in 6-OHDA model | |||
| ↓ haloperidol-induced catalepsy | |||
| ↓ LIDs in MPTP model | |||
| ↑ “on time” and “on time without disabling dyskinesia” in MPTP model | |||
| Calcium Channel Blockers | Cav1.3 Channel Blockers Isradipine | ↑ survival of DA nigral neurons in MPTP and 6-OHDA models | Chan et al., 2007, 2010; Schuster et al., 2009; Ilijic et al., 2011; Kang et al., 2012 |
| ↓ degeneration of striatal DA fibers in 6-OHDA model | |||
| ↓ development of motor deficits in MPTP model | |||
| ↓ LIDs and AIMS in 6-OHDA model | |||
| Glucagon-like Peptide 1 Agonists | GLP-1 Analogs Exendin-4 | ↑ survival of DA neurons, DA levels in MPTP model | Harkavyi et al., 2008; Li et al., 2009 |
| ↑ motor function in MPTP model | |||
| ↑ rescue of DA neurons, DA levels and apomorphine-induced circling in 6-OHDA and LPS models | |||
| Iron Chelators | Chelators Desferrioxamine, VK-28, Clioquinol, M30, Deferiprone | ↑ striatal DA and normal motor behavior in 6-OHDA model | Ben-Shachar et al., 1991, 1992; Lan and Jiang, 1997; Kaur et al., 2003; Shachar et al., 2004; Youdim et al., 2004; Youdim, 2012; Gal et al., 2005 |
| ↑ survival of DA neurons and striatal DA content in MPTP model | |||
| Anti-inflammatories | Non-selective NSAIDs Aspirin, Salicylic acid, Indomethacin | ↑ survival of DA neurons in MPTP model | Aubin et al., 1998; Ferger et al., 1999; Kurkowska-Jastrzebska et al., 2002 |
| ↑ striatal DA in MPTP model | |||
| ↓ microglial activation and lymphocyte infiltration in MPTP model | |||
| Selective COX-2 inhibitors Meloxicam, Celocoxib | ↑ survival of DA neurons in 6-OHDA and MPTP models | Teismann and Ferger, 2001; Sanchez-Pernaute et al., 2004 | |
| ↑ striatal DA in MPTP model | |||
| ↑ locomotor activity in MPTP model | |||
| ↓ microglial activation in 6-OHDA model | |||
| Gene Therapy | Non-Growth Factors AADC, GAD | ↑ DA levels | Fan et al., 1998; Leff et al., 1999; Sanchez-Pernaute et al., 2001; Luo et al., 2002; Lee et al., 2005; Emborg et al., 2007 |
| ↑ behavioral recovery in 6-OHDA model | |||
| ↑ survival of DA neurons and DA levels in 6-OHDA model | |||
| ↓ rotation rates in 6-OHDA model | |||
| ↑ improvement in bradykinesia, gross motor skills, and tremor in MPTP model | |||
| Neurotrophic Factors | GDNF | ↑ density of TH positive fibers and DA levels in 6-OHDA and MPTP models | Sauer et al., 1995; Tomac et al., 1995; Miyoshi et al., 1997; Zhang et al., 1997; Gerhardt et al., 1999; Kirik et al., 2000a,b; Palfi et al., 2002; Wang et al., 2002; Eslamboli et al., 2003; Eberling et al., 2009; Johnston et al., 2009 |
| ↑ survival of DA neurons and DA levels in 6-OHDA model | |||
| ↓ parkinsonism and LIDs in MPTP model | |||
| ↑ behavioral recovery in 6-OHDA and MPTP models | |||
| Neurturin | ↑ survival of DA neurons and DA levels in 6-OHDA and MPTP models | Rosenblad et al., 1999; Oiwa et al., 2002; Kordower et al., 2006; Gasmi et al., 2007a,b; Herzog et al., 2007 | |
| ↑ density of TH positive fibers | |||
| ↑ motor function in MPTP model |
Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; 6-OHDA, 6-hydroxydopamine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; AIMs, abnormal involuntary movements; AADC, aromatic l-amino acid decarboxylase; DA, dopamine; GDNF, glial derived neurotrophic factor; GAD, glutamic acid-decarboxylase; LIDs, L-Dopa-induced dyskinesias; L-Dopa, levodopa; LPS, lipopolysaccharide; NMDA, N-methyl-D-aspartate; NSAIDs, non-steroidal anti-inflammatory drugs; TH, tyrosine hydroxylase.