Delayed treatment with melatonin enhances electrophysiological recovery following transient focal cerebral ischemia in rats

Abstract

: Melatonin has been reported to reduce infarct volumes induced by transient middle cerebral artery (MCA) occlusion. We examined whether melatonin could improve electrophysiological and neurobehavioral recoveries in rats after 72 hr of reperfusion following 1.5 hr of MCA occlusion. Melatonin (5 mg/kg) or vehicle was given intravenously at the commencement of reperfusion. Neurobehavioral outcome was serially examined, and somatosensory evoked potentials (SSEP) were recorded prior to ischemia and at 72 hr after the onset of reperfusion. Brain infarction was assessed upon killing. Before ischemia‐reperfusion, stable SSEP waveforms were consistently recorded after individual fore‐ or hindpaw stimulation. The amplitude between the first positive (P1) and the first negative (N1) peaks and the P1 latency did not differ significantly between controls and melatonin‐treated animals. At 72 hr of reperfusion, controls had severely depressant SSEPs recorded from ischemic fore‐ and hindpaw cortical fields, and the amplitudes decreased to 36 and 35% of baselines, respectively (P < 0.001). These animals also had transcallosal electrophysiological diaschisis in the SSEPs recorded at the contralateral hindpaw cortical field (P < 0.01). Relative to controls, melatonin‐treated animals not only had significantly improved amplitudes of the SSEPs recorded from both ischemic fore‐ and hindpaw cortical fields, by 33 and 37% of baselines, respectively (P < 0.001), but also exhibited diminished transcallosal electrophysiological diaschisis following ischemia‐reperfusion. In addition, melatonin improved sensory and motor neurobehavioral outcomes by 40 and 28%, respectively (P < 0.001), and reduced cortical and striatal infarct sizes by 32 and 40%, respectively (P < 0.05). Thus, delayed intravenous administration with melatonin both enhances electrophysiological and neurobehavioral recoveries and reduces cortical and striatal infarct sizes after cerebral ischemia and reperfusion injury.

Therapeutical Implications of Melatonin in Alzheimer’s and Parkinson’s Diseases

“…Besides the animal models of AD and PD discussed below, melatonin has been shown to lower neural damage due to cadmium toxicity (Poliandri et al 2006 ;Jimenez-Ortega et al 2011 ), hyperbaric hyperoxia (Shaikh et al 1997 ;Pablos et al 1997 ), δ-aminolevulinic acid toxicity (Princ et al 1997 ;Carneiro and Reiter 1998 ;Onuki et al 2005 ), γ radiation (Erol et al 2004 ;Shirazi et al 2011 ;Taysi et al 2008 ), focal ischemia (Lee et al 2004 ;Tai et al 2011 ), brain trauma (Beni et al 2004 ;Tsai et al 2011 ;Kabadi and Maher 2010 ), and a number of neurotoxins (Reiter et al 2010 ).…”

Cinnamophilin Inhibits Neutrophilic Respiratory Burst and Protects Against Ischemia-Reperfusion Brain Damage

“…Two neurologic grading systems were used: (i) a sensorimotor grading scale modified from previously published methods [30] with five categories (0-4) for forward and sideways visual placing tests of the affected forelimb and five categories (0-4) for motor outcome and (ii) a grading scale of 0-28 developed by Clark et al [31].…”

Delayed Treatment with Carboxy-PTIO Permits a 4-h Therapeutic Window of Opportunity and Prevents Against Ischemia-Induced Energy Depletion Following Permanent Focal Cerebral Ischemia in Mice

“…The brain was then rapidly removed, cut into 2 mm coronal sections using a mouse brain matrix (RBM 2000C, ASI Instrument, Inc., Warren, MI) and stained according to the standard 2,3,5-triphenyltetrazolium chloride (TTC) method [7,[21][22][23][24]. Each slice was drawn using a semi-automated computerized image analyzer (MCID, Imaging Research Inc., ON, Canada).…”

“…The calculated infarction areas were then compiled to obtain the infarct volumes per brain (in mm 3 ). Infarct volumes were expressed as a percentage of the contralateral hemisphere volume by using an ''indirect method'' to compensate for edema formation in the ipsilateral hemisphere [7,[21][22][23][24].…”

“…A modification of previously published methods was used to evaluate the sensorimotor integrity [7,[21][22][23]31]. Accordingly, five categories of motor neurologic findings were scored: 0, no observable deficit; 1, forelimb flexion; 2, forelimb flexion and decreased resistance to lateral push; 3, forelimb flexion, decreased resistance to lateral push and unilateral circling; 4, forelimb flexion, unable or difficult to ambulate.…”