Table 2.
Apocynin use in vivo in experimental CNS disorder models
| Disease | Model | Species | Dose | Way/duration admin | Therapeutic benefit | References |
|---|---|---|---|---|---|---|
| AD | Transgenic mice overexpressing human APP with two mutations (Tg19959) | Mice | 300 mg/kg | In the drinking water from 1 to 5 months of age | No improvement of behavior and neuropathologic signs (amyloid deposition, microgliosis and tau phosphorylation) | [34] |
| Transgenic mice overexpressing human APP with the Swedish and London mutations hAPP(751)(SL) | Mice | 10 mg/kg | Daily gavage from 4 to 8 months of age | Reduced plaque size and microglia proliferation in the cortex | [95] | |
| PD | Sequential injections i.p of paraquat (10 mg/kg/3 days) | Mice | 200 mg/kg | i.p. | Decrease in dopaminergic neuronal loss and microglia proliferation in the substantia nigra | [31] |
| ALS | SOD1 G93A | SOD1 G93A transgenic mice | 30, 150, and 300 mg/kg/day | In drinking water starting at day 14 of age | Increased survival by 56, 80 and 113 days respectively | [54] |
| 150, 300 and 750 mg/kg/day | In drinking water starting at day 21 and 100 of age | No increased survival for any treatment protocol | [152] | |||
| 150 mg/kg | Way not specified, starting at day 50 of age | Increased survival by 5 days | [89] | |||
| Schizophrenia | i.p. subanesthetic ketamine injection (30 mg/kg) on two consecutive days at around 4 pm | C57BL/6 J mice | 5 mg/kg/day | Per os in the drinking water for a total of seven days before ketamine inections | Decreased oxidative stress and loss of parvalbumin | [11] |
| Post-weaning social isolation for 7 weeks | Wistar rats | 5 mg/kg/day | Per os in drinking water for 7 weeks | Decreased oxidative stress, prevented parvalbumin loss and behavioural alterations | [136] | |
| Ischemic stroke | 2 h MCA occlusion with a poly-l-lysine-coated monofilament suture followed by 22 h reperfusion | C57BL/6 J mice |
2.5 mg/kg NOT at higher doses of 3.75 and 5 mg/kg |
i.v. 30 min before reperfusion | Improved neurological function, reduced infarct volume, and reduced the incidence of cerebral hemorrhage | [150] |
| 2 h MCA occlusion with intraluminal filament followed by 24 h reperfusion | C57BL/6 J mice | 2.5 mg/kg | i.v. at the onset of reperfusion | Reduced infarct volume, better neurological function, less BBB disruption and hemorrhage, decreased MMP-9 expression and prevention of tight junction protein loss | [165] | |
| 1.5 h MCA occlusion with a nylon monofilament (4-0) followed by 2 h reperfusion | Sprague–Dawley rats | 50 mg/kg | i.p. injection 30 min prior to reperfusion | Reduced NOX activity, superoxide levels and infarct size | [149] | |
| 0.5 h MCA occlusion followed by 23.5 h reperfusion | C57Bl/6 J mice | 2.5 mg/kg | i.p. injection 0.5 h before ischaemia | Reduced total infarct volume, neurological impairment, superoxide production and mortality | [66] | |
| 75 min MCA occlusion using a 6-0 coated suture followed by reperfusion | C57BL/6 J mice | 4 mg/kg | i.p. injection 5 min before suture withdrawal | Reduced oxidative stress, 50% less brain infarction and 70% less cleaved spectrin | [27] | |
| 90 min MCA occlusion with 22.5 h reperfusion | Sprague–Dawley rats | 30 mg/kg | i.p. injection 1 h before the onset of MCAO | Reduced the MMP-9 increase, BBB damage brain edema, and NOX activity | [91] | |
| 2 h MCA occlusion with a 4–0 nylon monofilament followed by 22 h reperfusion | Wistar rats | 5 mg/kg | i.p. injection 5 min before reperfusion | Reduction in infarct size, inflammation and cellular death | [45] | |
| MCA occlusion with a silicone-coated 8-0 monofilament for 2 h followed by 22 h reperfusion | C57BL/6 mice | 0.4, 4, and 40 mg/kg | i.v. 1 h before induction of MCAO | 40 mg/kg prevented BBB disruption | [70] | |
| 90 min MCA occlusion followed by 1, 4, 8, 24 h reperfusion | Sprague–Dawley rats (7 weeks old) | 5 mg/kg | i.p. 30 min before induction of MCAO and 5 min after reperfusion | Attenuated protein carbonylation in the postsynaptic density proteins and cerebral infarct volume | [111] | |
| Occlusion of both common carotid arteries | Mongolian gerbils | 5 mg/kg | i.p. 30 min before ischemia | Attenuated oxidative stress, neuronal degeneration and glia activation | [160] | |
| MCA occlusion with tissue plasminogen activator | Young (3-4 months) and aged (18-20 months) rats | 5 mg/kg | i.p. 30 min before induction of MCAO | in aged rats increased mortality rate and failed to improve the functional outcome, total infarct volume, edema formation, and BBB permeability | [73] | |
| Transient global cerebral ischemia induced by bilateral common carotid artery occlusion for 22 min followed by 3, 6 and 72 h reperfusion | C57BL/6 | 2.5 mg/kg | i.v. 15 min befor ischemia | Attenuated oxidative injury, microglial activation, and neuronal death | [167] | |
| 1 h MCA followed by 24 h reperfusion | C57BL/6 mice | 4 mg/kg | i.v. 1 h after MCAO | No reduction of infarct size | [77] | |
| Hemorrhagic stroke | Endovascular perforation of the right anterior cerebral artery | Rats | 50 mg/kg | i.p. injection 3 times daily for 2 days | Enlarged basilar artery diameter, reduced neurological deficits, decreased NOX activity and superoxide production | [172] |
| Intracerebral haemorrhage | Rats | 3, 10 and 30 mg/kg | i.p. 2 h after haemorrhage | No neuroprotective effect | [151] | |
| Glycerol-induced intraventricular hemorrhage (IVH) in prematurely delivered (E29) rabbit pups by intraperitoneal infusion of 50% glycerol (6.5 g/kg) solution 2 h after birth | Rabbit | 2.5 mg/kg per dose | i.v. injections at 3 and 12 h after IVH | Reduced ROS generation and cell death | [174] | |
| Ischemic brain injury associated with hyperglicemia | Transient bilateral common carotid artery occlusions and hyperglycemia | C57Bl/6 J mice | 15 mg/Kg |
i.p. injection before reperfusion |
Decreased neuronal superoxide production and death | [148] |
| Ischemic brain injury associated with chronic alcohol consumption |
Liquid diet with alcohol (6.4% v/v) for 8 weeks, 2-h middle cerebral artery occlusion followed by 24-h reperfusion |
Sprague–Dawley rats |
Acute: 5 mg/kg chronic: 7.5 mg/kg/day |
Acute: i.p. 30 min before MCAO Chronic: per os, 4 weeks prior to MCAO |
Both treatments reduced infarct volume, improved neurological outcome, attenuated superoxide production in alcohol-fed rats | [171] |
| Ischemic brain injury associated with hypertension | Two renal arteries were constricted bilaterally with two ring-shaped silver clips | Stroke-prone renovascular hypertensive rats | 1.5 mmol/L | Per os in the drinking water for 28 days beginning on the 5th week after the operation | Decrease in the expression of p22phox protein and fibronectin levels in the cerebral vasculature | [32] |
| Ischemic brain injury associated with excess salt consumption | 8% sodium diet from 11 weeks of age during 1, 2, or 4 weeks | Stroke-prone spontaneously hypertensive rats | 0.6 mmol/kg per day | Per os in the drinking water for 4 weeks | Reduced oxidative stress, cell death and stroke incidence | [166] |
| Neonatal hypoxic-ischemic injury |
On postnatal day 7, left common carotid artery was cauterized over a length of 5 mm. 2 to 4 h after surgery, the rats were exposed to 100% oxygen at 37°C for 2 h |
Wistar rats | 4 mg/kg | i.p. injection, first dose following hyperoxia and again the following morning | Increased NO and reduced O2 − | [37] |
| Huntington disease | Intrastriatal injection of quinolinic acid (QUIN) 240 nmol/ul | Wistar rats | 5 mg/kg | i.p. 30 min before and 1 h after QUIN injection or only 30 min after QUIN injection | Decreased lipid peroxidation, circling behavior, and histological damage | [96] |
| Insulin-induced hypoglycemia | Hypoglicemia followed by glucose reperfusion (infusion of 50% glucose in Krebs-Henseleit buffer) | Sprague–Dawley rats | 15 mg/kg | i.p. injection before the start of glucose reperfusion | Reduced neuronal death | [147] |
| NMDA receptor-dependent excitotoxicity | Injections of 6 nmol of NMDA in the right hippocampus | C57BL/6 mice | 15 mg/kg | i.p. injection 20–30 min before the NMDA injections | Prevented superoxide production and neuronal death | [20] |
| Epilepsy | Pilocarpine injections in hippocampus | Wistar rats | 10 mg/kg | In the drinking water 7 days prior to induction of status epilepticus | Decreased ROS production and neurodegeneration | [122] |
| Anxiety | l-buthionine-(S,R)-sulfoximine (BSO, 300 mg/kg i.p.) 48 and 24 h before behavioral testing | ICR mice | 3 mg/kg | i.p. injection 30 min before each BSO treatment | Reduced anxiety-like behavioral | [101] |
| Obstructive sleep apnea | Long-term intermittent hypoxia | C57BL/6 J mice | 3 mg/kg/day | Subcutaneously by way of microosmotic pump for 8 weeks | Conferred resistance to hypersomnolence, reduced oxidative damage and cathecolaminergic neuron death in wake- active brain regions | [169, 173] |
| Long-term intermittent hypoxia | Sprague–Dawley rats | 3 mg/kg/day in 50 ul of 0.9% saline |
Intragastrically 3 days before |
Amelioration of spatial learning deficits, decreased oxidative stress and apoptosis | [60] |