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Fulltext Differential Action of Connexin Hemichannel and Pannexin Channel Therapeutics for Potential Treatment of Retinal Diseases

Mat Nor MN, Rupenthal ID, Green CR, Acosta ML

Int J Mol Sci, 2021 Feb 10;22(4).
PMID: 33578721 DOI: 10.3390/ijms22041755

Dysregulation of retinal function in the early stages of light-induced retinal degeneration involves pannexins and connexins. These two types of proteins may contribute to channels that release ATP, leading to activation of the inflammasome pathway, spread of inflammation and retinal dysfunction. However, the effect of pannexin channel block alone or block of both pannexin channels and connexin hemichannels in parallel on retinal activity in vivo is unknown. In this study, the pannexin channel blocker probenecid and the connexin hemichannel blocker tonabersat were used in the light-damaged rat retina. Retinal function was evaluated using electroretinography (ERG), retinal structure was analyzed using optical coherence tomography (OCT) imaging and the tissue response to light-induced injury was assessed immunohistochemically with antibodies against glial fibrillary acidic protein (GFAP), Ionized calcium binding adaptor molecule 1 (Iba-1) and Connexin43 (Cx43). Probenecid did not further enhance the therapeutic effect of connexin hemichannel block in this model, but on its own improved activity of certain inner retina neurons. The therapeutic benefit of blocking connexin hemichannels was further evaluated by comparing these data against results from our previously published studies that also used the light-damaged rat retina model. The analysis showed that treatment with tonabersat alone was better than probenecid alone at restoring retinal function in the light-damaged retina model. The results assist in the interpretation of the differential action of connexin hemichannel and pannexin channel therapeutics for potential treatment of retinal diseases.
Fulltext No Differences in Energy Cost of a Predetermined Exercise among Young Overweight/Obese and Undernourished Individuals

Muralidhara DV, Mat Nor MN, Zubaidi AL

Int J Yoga, 2018 5 15;11(2):148-151.
PMID: 29755224 DOI: 10.4103/ijoy.IJOY_78_16

Background: Physical activity is an integral part of one's daily life. Obese (Ob) and undernourished (UN) persons are known to underperform physically as compared to normal weight (N) individuals. In this study, we have measured the energy spent to perform a prefixed exercise on treadmill walking and basal heart rate and blood pressure. Body mass index (BMI) and body fat of participating individuals were assessed. Fasting blood sugar and lipid profile were also evaluated.
Materials and Methods: Eighty-three young individuals (male: 41; female: 42) of medical faculty, Universiti Sultan Zainal Abidin, who volunteered for the study, were recruited. The mean age of the individuals was 19.8 ± 0 years (P < 1.08). The individuals were grouped as N, UN/underweight, and overweight (Ow)/Ob based on BMI.
Results: The results of the study revealed that there were no differences in the energy spent on performing the predetermined treadmill walking of 20 min duration among the three groups (a mean of 78 and 70 calories in all male and female subgroups, respectively). The distance covered by the males was 1.6 km while the females covered 1.4 km on treadmill walking in 20 min time. Basal blood pressure and heart rate and fasting blood sugar did not reveal any significant difference among the groups. However, total cholesterol and triglyceride levels were marginally higher in the Ow/Ob groups of male and female individuals as compared to other groups.
Conclusion: Since the study individuals were very young and competitive by nature and possibly had no major metabolic disturbances, the differences in physical activity performances were not obvious. Possibly, such differences would become apparent only at later stages of life as age advances or when the intensity and duration of exercise are set at higher levels.
Fulltext Connexin Hemichannel Block Using Orally Delivered Tonabersat Improves Outcomes in Animal Models of Retinal Disease

Mat Nor MN, Rupenthal ID, Green CR, Acosta ML

Neurotherapeutics, 2020 Jan;17(1):371-387.
PMID: 31637594 DOI: 10.1007/s13311-019-00786-5

Increased Connexin43 hemichannel opening is associated with inflammasome pathway activation and inflammation in a range of pathologies including ocular disorders, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). In this study, the effect on retinal function and morphology of clinically safe doses of orally delivered tonabersat, a small molecule connexin hemichannel blocker, was investigated in the light-damaged retina animal model of dry AMD and in a spontaneous rat model of DR. Clinical parameters (fundus imaging, optical coherence tomography (OCT), and electroretinography) and inflammatory markers (immunohistochemistry for Iba-1 microglial marker, astrocyte marker glial fibrillary acidic protein, and Connexin43 protein expression) were assessed. Tonabersat treatment reduced inflammation in the retina in parallel with preservation of retinal photoreceptor function when assessed up to 3 months post light damage in the dry AMD model. In the DR model, clinical signs, including the presence of aneurysms confirmed using Evans blue dye perfusion, were reduced after daily tonabersat treatment for 2 weeks. Inflammation was also reduced and retinal electrical function restored. Tonabersat regulates assembly of the inflammasome (NLRP3) through Connexin43 hemichannel block, with the potential to reduce inflammation, restore vascular integrity and improve anatomical along with some functional outcomes in retinal disease.
Fulltext Anthropometry and body composition status during Ramadan among higher institution learning centre staffs with different body weight status

Rohin MA, Rozano N, Abd Hadi N, Mat Nor MN, Abdullah S, Dandinasivara Venkateshaiah M

ScientificWorldJournal, 2013;2013:308041.
PMID: 24311975 DOI: 10.1155/2013/308041

This study was done to observe the anthropometry and body composition changes before, during, and after the holy month of Ramadan. This study was carried out on 46 staff from one of the local universities, which comprised of 14 males and 32 females ranging in age from 25 to 40 years old. There were four sessions done to complete this study, namely, a week before Ramadan (T1), 1st week of Ramadan (T2), 3rd week of Ramadan (T3), and a month after Ramadan (T4). All subjects were assessed according to weight, body circumference, and body composition status. It was found that subjects with different weight status showed a significant reduction in weight (P < 0.01) but no significant reduction in body fat percentage (P < 0.05). The findings suggest that weight reduction does not promise a reduction in body fat. Changes in neck circumference were only found in normal subjects. Hence, it can be said that overweight and obese subjects showed no changes in anthropometry status during Ramadan. No changes in body composition were reported in all three weight groups except for trunk body fat. In conclusion, normal subjects showed significant changes in various anthropometry parameters, but overweight and obese subjects showed no obvious difference.
Fulltext Hyper-reflective dots in optical coherence tomography imaging and inflammation markers in diabetic retinopathy

Mat Nor MN, Guo CX, Green CR, Squirrell D, Acosta ML

J Anat, 2023 Oct;243(4):697-705.
PMID: 37222261 DOI: 10.1111/joa.13889

The aim of this study is to correlate small dot hyper-reflective foci (HRF) observed in spectral domain optical coherence tomography (SD-OCT) scans of an animal model of hyperglycaemia with focal electroretinography (fERG) response and immunolabelling of retinal markers. The eyes of an animal model of hyperglycaemia showing signs of diabetic retinopathy (DR) were imaged using SD-OCT. Areas showing dot HRF were further evaluated using fERG. Retinal areas enclosing the HRF were dissected and serially sectioned, stained and labelled for glial fibrillary acidic protein (GFAP) and a microglial marker (Iba-1). Small dot HRF were frequently seen in OCT scans in all retinal quadrants in the inner nuclear layer or outer nuclear layer in the DR rat model. Retinal function in the HRF and adjacent areas was reduced compared with normal control rats. Microglial activation was detected by Iba-1 labelling and retinal stress identified by GFAP expression in Müller cells observed in discrete areas around small dot HRF. Small dot HRF seen in OCT images of the retina are associated with a local microglial response. This study provides the first evidence of dot HRF correlating with microglial activation, which may allow clinicians to better evaluate the microglia-mediated inflammatory component of progressive diseases showing HRF.
Fulltext Connexin therapeutics: blocking connexin hemichannel pores is distinct from blocking pannexin channels or gap junctions

Acosta ML, Mat Nor MN, Guo CX, Mugisho OO, Coutinho FP, Rupenthal ID, et al.

Neural Regen Res, 2021 Mar;16(3):482-488.
PMID: 32985469 DOI: 10.4103/1673-5374.290097

Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases. Some of these compounds are now in clinical trials, but for many of them, the literature is inconclusive about the molecular effect on the tissue, despite evidence of functional recovery. Blocking the different channel types has distinct physiological and pathological implications and this review describes current knowledge of connexin and pannexin protein channels, their function as channels and possible mechanisms of the channel block effect for the latest therapeutic compounds. We summarize the evidence implicating pannexins and connexins in disease, considering their homeostatic versus pathological roles, their contribution to excesive ATP release linked to disease onset and progression.